Organocatalytic Asymmetric Epoxidation and Aziridination of Olefins and Their Synthetic Applications

Review
pubs.acs.org/CR
Organocatalytic Asymmetric Epoxidation and Aziridination of Olefins

and Their Synthetic Applications
Yingguang Zhu, Qian Wang, Richard G. Cornwall, and Yian Shi*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
2.7. Chiral Amine or Chiral Amine Salt-Catalyzed
Epoxidation 8242
2.8. Aspartic Acid-Based Peptide-Catalyzed Ep-
oxidation 8243
3. Organocatalyzed Asymmetric Aziridination of
Olefins 8243
3.1. Chiral Quaternary Ammonium Salt-Cata-
lyzed Aziridination 8243
3.2. Amine-Promoted Aziridination via Amini-
mide 8244
3.3. Aziridination via Iminium/Enamine Catalysis 8245
3.3.1. Pyrrolidine-Based Catalysts 8245
CONTENTS 3.3.2. Chiral Amine Salt Catalysts 8246
1. Introduction 8199 3.4. Chiral Amino Thiourea-Catalyzed Aziridina-
2. Organocatalyzed Asymmetric Epoxidation of tion 8247
Olefins 8200 4. Conclusion 8247
2.1. Phase-Transfer Catalysts 8200 Author Information 8248
2.1.1. Cinchona Alkaloid-Derived Quaternary Corresponding Author 8248
Ammonium Salts 8200 Notes 8248
2.1.2. Other Quaternary Ammonium Salts 8203 Biographies 8248
2.1.3. Guanidinium Salts 8204 References 8249
2.1.4. Crown Ether-Type Catalysts 8204
2.2. Peptide-Type Catalysts 8204
2.2.1. Polypeptide-Catalyzed Epoxidation 1. INTRODUCTION
under Triphasic Conditions 8204 Epoxides and aziridines are extremely versatile synthetic
2.2.2. Polypeptide-Catalyzed Epoxidation intermediates1,2 and present in a large array of natural products
under Biphasic Conditions 8206 and biologically active molecules (Figure 1).1f,3,4 In addition,
2.2.3. Polypeptide-Catalyzed Epoxidation
under Homogeneous Conditions 8208
2.2.4. Epoxidation with Peptides Containing
Unnatural Amino Acids 8209
2.2.5. Mechanistic Insights 8210
2.3. Chiral Bifunctional Base-Catalyzed Epoxida-
tion 8210
2.3.1. Chiral Guanidines 8210
2.3.2. Chiral β-Amino Alcohols 8210
2.3.3. Cinchona Alkaloid-Derived Thioureas 8212
2.4. Epoxidation via Iminium/Enamine Catalysis 8213
2.4.1. Pyrrolidine-Based Catalysts 8213
2.4.2. Chiral Amine Salt Catalysts 8215
2.5. Chiral Ketone-Catalyzed Epoxidation 8217
2.5.1. Methodology Development 8217
2.5.2. Synthetic Applications 8225
2.6. Chiral Iminium Salt-Catalyzed Epoxidation 8238
2.6.1. Dihydroisoquinoline-Based Iminium
Salts 8239 Figure 1. Epoxide or aziridine-containing biologically active molecules.
2.6.2. Binaphthylazepinium-Based Iminium
Salts 8240 Special Issue: 2014 Small Heterocycles in Synthesis
2.6.3. Biphenylazepinium-Based Iminium Salts 8240
2.6.4. Exocyclic Iminium Salts 8242 Received: February 3, 2014
Published: May 1, 2014
© 2014 American Chemical Society 8199 dx.doi.org/10.1021/cr500064w | Chem. Rev. 2014, 114, 8199−8256
Chemical Reviews Review
epoxides are proposed to be biosynthetic intermediates for the Scheme 1. Catalytic Cycle for Asymmetric Epoxidation with
rapid construction of complex polycyclic natural products such Phase-Transfer Catalysts
as (+)-aurilol and brevetoxin B (Figure 2).5 The stereo-
chemistry possessed by the epoxides and aziridines in
biologically active molecules necessitates their enantioselective
synthesis.
2.1.1. Cinchona Alkaloid-Derived Quaternary Ammo-

nium Salts. In 1976, Wynberg and co-workers utilized the
cinchona alkaloid-derived quaternary ammonium salt 1 to
catalyze epoxidation of α,β-unsaturated ketones with up to 45%
ee (Figure 3).13 Onda reported the epoxidation of an ester-
Figure 2. Examples of polycyclic natural products from polyepoxide substituted naphthoquinone in 78% ee using catalyst 1 (Figure
precursors. 3).14
Asymmetric catalysis using metals has seen widespread

success in the past decades. In recent years, the use of small
nonmetal organic molecules as catalysts has witnessed
significant development, particularly since the mid-1990s, and
established its prominence in synthetic chemistry. To
distinguish from metal-catalyzed processes (organometallic
catalysis),6a these nonmetal-catalyzed reactions are often
referred to as organic catalysis (Kagan 1999),6a organocatalysis,
or organocatalytic (MacMillan 2000).6b The organocatalyzed
asymmetric epoxidation of olefins is an important part of this
field, and some of these systems are very early examples of Figure 3. Asymmetric epoxidation using catalyst 1.
effective and useful organocatalytic processes. A number of
organocatalyzed systems have also been developed for
asymmetric aziridination of olefins. This review will highlight In 1998, Taylor and co-workers accomplished the syntheses
various advances in organocatalytic asymmetric epoxidation and of three members of the manumycin family, (−)-alisamycin
aziridination of olefins as well as their synthetic applications. (5), (+)-MT 35214 (6), and (+)-manumycin A (7) (Scheme
2).15 Key intermediate 4 was synthesized via epoxidation of
2. ORGANOCATALYZED ASYMMETRIC EPOXIDATION enone 3 using cinchonidine-derived catalyst 2 in 32% yield and
OF OLEFINS 89% ee and can be obtained in >99% ee after recrystalliza-
Asymmetric epoxidation of olefins presents an especially tion.15c N-Benzylcinchoninium chloride (8) was employed in
attractive approach to chiral epoxides.7 Great success has the syntheses of palmarumycins and (−)-preussomerin G by
been achieved with metal-catalyzed asymmetric epoxidation of Barrett and co-workers in 2002 (Scheme 3).16 Asymmetric
olefins such as epoxidation of allylic alcohols,8 related
heteroatom-containing olefins,9 and unfunctionalized ole- Scheme 2. Synthesis of the Members (5−7) of the
fins,9b,10 as well as nucleophilic epoxidation of electron- Manumycin Family
deficient olefins.11 Complementary to metal-catalyzed pro-
cesses, organocatalytic asymmetric epoxidation has also proven
to be highly effective for synthesis of chiral epoxides.12 This
section will highlight the progress in this area including phase-
transfer catalysts, peptide-type catalysts, chiral ketone and
iminium salt catalysts, and chiral amine catalysts, etc.
2.1. Phase-Transfer Catalysts
Use of phase-transfer catalysts (PTCs) was first reported
approximately 40 years ago for asymmetric epoxidation of
olefins. Chiral epoxides are obtained from electron-deficient
olefins (mostly enones) with catalysts such as quaternary
ammonium salts and crown ethers in the presence of oxidants
(Scheme 1).12
8200 dx.doi.org/10.1021/cr500064w | Chem. Rev. 2014, 114, 8199−8256
Scheme 3. Synthesis of Palmarumycin C2 (10) and

(−)-Preussomerin G (11)
epoxidation of enone 9 with catalyst 8 in the presence of TBHP Figure 6. Epoxidation of conformationally fixed enones with catalyst
gave palmarumycin C2 (10) in 81% yield and >95% ee, which 13b.
was further converted into (−)-preussomerin G (11).
Quaternary ammonium salt catalysts with various nitrogen
substitutions have been investigated (Figure 4). Kawaguchi and
Figure 7. Epoxidation of enones with catalysts 14−16.
catalysts. Up to 84% ee was obtained for epoxidation of 2-

isopropyl-1,4-naphthoquinone with catalyst 16 (Figure 7).22
Figure 4. Quaternary ammonium salt catalysts 12−18.
In 2013, Shibata and co-workers reported that β-trifluor-
omethyl-β,β-disubstituted enones could be epoxidized in high
co-workers reported catalyst 12 with a N-fluorenyl group in yields and high enantioselectivities with N-3,5-bis-
1986, giving up to 61% ee for epoxidation of cyclic enones.17 In (trifluoromethyl)benzyl-substituted catalyst 17 in the presence
1998, Arai, Shioiri, and co-workers reported that the of methylhydrazine and air (Figure 4 and Table 1).23 It was
substituents on the phenyl ring of the N-benzyl unit in the
cinchona alkaloid-derived catalysts played an important role in Table 1. Epoxidation of β,β-Disubstituted Enones with
the asymmetric induction. Up to 92% ee was obtained for Catalyst 17
epoxidation of chalcones using catalyst 13a (Figure 5).18
entry Ar1 Ar2 yield (%) dr ee (major) (%)

1 Ph Ph 91 95:5 99
2 4-MeOC6H4 Ph 91 94:6 98
3 Ph 2-MeC6H4 99 96:4 96
4 Ph 4-O2NC6H4 98 94:6 96
5 Ph 2-naphthyl 99 94:6 98
Figure 5. Epoxidation of enones with catalyst 13. proposed that H2O2 was likely to be generated in situ from
methylhydrazine and air and to act as the oxidant. In their
studies, Chen and co-workers found that quinidinium catalyst
However, only 2% ee was obtained when the secondary alcohol 18 (Figure 4), bearing a pentafluorobenzyl group, was very
of 13a was protected as an allyl ether. In 2001, Adam and co- effective for epoxidation of β-trifluoromethyl-β,β-disubstituted
workers reported that up to 98% ee was obtained for enones in the presence of H2O2, giving up to 96% yield and
conformationally rigid enones using catalyst 13b and sterically 99.7% ee (Table 2).24 The resulting α,β-epoxy ketone 19 could
demanding hydroperoxides as the oxidants (Figure 6).19 be converted into potentially useful β-trifluoromethyl-β-
Epoxidation of enones with catalysts bearing sterically bulky hydroxy ketone 20 in 91% yield via reduction with Zn and
N-substituents (14,20 15,21 and 1622) (Figure 4) has also been NH4Cl (Scheme 4). The hydrogen-bonding and the π−π
investigated. In 1998, Arai, Shioiri, and co-workers reported stacking interaction of the pentafluorobenzyl unit and the aryl
that 76% ee was obtained for 2-phenyl-1,4-naphthoquinone group of the substrate appear to be important contributing
with catalyst 14 (Figure 7).20a Berkessel and co-workers factors for the asymmetric induction during this reaction
showed that 2-methyl-1,4-naphthoquinone (vitamin K3) was (Figure 8).
epoxidized with catalyst 15, bearing a hydroxyl group on the The C-9 hydroxyl groups of quaternary ammonium salt
quinoline ring, in 85% ee (Figure 7).21 In 2002, Dehmlow and catalysts appear to be important for the enantioselectivity in
co-workers reported their studies on analogues of cinchona many cases.18,19b,21,24 However, as shown by Lygo25 and
alkaloids without the quinoline nitrogen atom as phase-transfer Corey,26 respectively, N-anthracenylmethyl-substituted ammo-
Table 2. Epoxidation of β,β-Disubstituted Enones with

Catalyst 18 and H2O2
yield ee (major)
entry R Ar (%) dr (%)
1 Ph Ph 93 50:1 99
2 Ph 4-ClC6H4 82 50:1 98
3 Ph 2-MeOC6H4 94 50:1 99.7
4 Ph 2-naphthyl 87 50:1 98
5 4-BrC6H4 Ph 96 50:1 97
6 3,5-Cl2C6H3 4-Br-3-MeC6H3 95 20:1 99
7 Et Ph 88 100:1 82 Figure 10. Epoxidation of enones with catalyst 21 or 22.
Scheme 4. Synthesis of β-Hydroxy Ketone 20 via Reduction Scheme 5. Synthesis of Epoxysuccinyl Peptide E-64c
of α,β-Epoxy Ketone 19
enones with catalyst 21b using KOCl as oxidant (Figure

11).26 The resulting α,β-epoxy ketones can be transformed into
Figure 8. Proposed transition state for epoxidation using catalyst 18.
nium salts with the C-9 hydroxyl groups being protected as

benzyl ethers are effective catalysts for epoxidation using
NaOCl and KOCl as oxidant (Figure 9). Both the nature of O-
Figure 11. Epoxidation of enones with catalyst 21b and KOCl.
other useful synthetic intermediates such as α,β-epoxy esters

and α-hydroxy esters (Scheme 6). The epoxidation is proposed
Scheme 6. Transformations of α,β-Epoxy Ketone

Figure 9. Quaternary ammonium salt catalysts 21 and 22.
and N-substituents and the choice of the oxidant are crucial for
the enantioselectivity. For example, in 1998, Lygo and co-
workers reported that (E)-chalcone was epoxidized in 90% to proceed via a transition state described in Figure 12.26 The
yield and 86% ee with catalyst 21a and NaOCl (Figure 10).25a rigidity of the catalyst allows it to adopt a certain three-
The ee’s were further improved by optimizing the reaction dimensional arrangement, which brings the substrate and
conditions (Figure 10).25c Allylic alcohols can be directly oxidant into a favorable proximity for the enantioselectivity via
converted to α,β-epoxy ketones in 78−87% ee under the electrostatic and van der Waals interactions.
epoxidation conditions.27 Epoxidation with catalyst 21b was Trichloroisocyanuric acid (TCCA) was also found to be an
used in the synthesis of epoxysuccinyl peptide E-64c (a cysteine effective oxidant for epoxidation with catalyst 21b as reported
protease inhibitor) (Scheme 5).28 by Liang and co-workers in 2003, with up to 96% ee for
In 1999, Corey and co-workers demonstrated remarkably epoxidation of chalcones (Figure 13).29 KOCl was believed to
high enantioselectivity (91−98.5% ee) for epoxidation of be formed in situ from TCCA and KOH and acted as the
which achieved up to 63% ee in the epoxidation of

cyclohexenone.17,33 A number of dimeric quaternary ammo-
nium salts with different linkers were examined for epoxidation
of enones by Jew, Park, and co-workers. Up to >99% ee was
achieved for diarylenones with 1 mol % catalyst 26 and 1 mol %
Figure 12. Proposed transition state for epoxidation using catalyst
Span 20 using H2O2 as the oxidant (Figure 17).34 The C-9
21b.
Figure 13. Epoxidation of chalcones with catalyst 21b and TCCA.
oxidant.29b Catalyst 21b was also used for epoxidation of α,β-

unsaturated sulfones by Dorow and Tymonko in 2006, giving Figure 17. Epoxidation of diarylenones with catalyst 26.
up to 82% ee for (E)-phenyl styrylsulfone with KOCl as
oxidant.30 hydroxyl group of the catalyst was shown to be crucial for high
Use of cinchonidine-derived catalyst 23 (Figure 14) for enantioselectivity. Both reactivity and enantioselectivity of the
epoxidation was reported by Kim and co-workers in 2003. Up epoxidation are greatly enhanced by addition of the surfactant.
In 2006, Wang and co-workers reported the epoxidation of
enones with poly(ethylene glycol)-linked cinchona quaternary
ammonium salts and TBHP, achieving up to 86% ee for
epoxidation of (E)-chalcone.35
2.1.2. Other Quaternary Ammonium Salts. Other
quaternary ammonium salt catalysts have been investigated
for asymmetric epoxidation of olefins (Figure 18). In 1983,
to 78% ee was obtained for epoxidation of 1,3-diarylenones

using NaOCl as oxidant.31 In 2010, Park, Jeong, and co-workers
showed that high ee’s could be achieved for epoxidation of
chalcones with catalyst 24 bearing a N-2,3,4-trifluorobenzyl
moiety (Figure 15).32 Figure 18. Quaternary ammonium salt catalysts 27−30.
In 1986, Kawaguchi and co-workers reported the epoxidation
of cyclic enones with C2-symmetric dimeric catalysts such as
cinchonine-derived quaternary ammonium salt 25 (Figure 16), Mazaleyrat reported binaphthyl-based catalyst 27, which
epoxidized (E)-chalcone with 37.1% ee in the presence of
H2O2.36 In 2004, Maruoka and co-workers showed that
binaththyl-based spiro quaternary ammonium salts (28),
containing two diaryl methanol groups, were highly effective
catalysts for epoxidation of enones (Figure 18).37 A variety of
α,β-epoxy ketones were obtained in 80−99% yield and 89−
99% ee using catalysts 28 with NaOCl as oxidant (Figure 19).
The hydroxyl groups of the catalyst appeared to be important
for the reactivity and enantioselectivity of the epoxidation.37 In
Figure 15. Epoxidation of chalcones with catalyst 24. 1994, Masaki and co-workers reported their studies on the
been examined for olefin epoxidation (Figure 22). Bakó and co-
workers reported monosaccharide-based crown ether-type
Figure 22. Crown ether-type phase-transfer catalysts 36−38.
catalysts 36 and 37 for the epoxidation,43 affording up to

>99% ee for chalcones with TBHP as oxidant (Figure 23).43e
Figure 19. Epoxidation of enones with catalyst 28.
epoxidation of (E)-chalcone (9.1% ee) with pyrrolidinium salts

29 and 30 as catalysts (Figure 18).38
2.1.3. Guanidinium Salts. In 2003, Murphy and co-
workers reported that C2-symmetric guanidinium salt 31
(Figure 20) was an active and enantioselective epoxidation
Figure 23. Epoxidation of enones with crown ether-type catalysts.
Both the monosaccharide moiety and the nitrogen substituent

of the catalyst were important for the reactivity and
enantioselectivity of the epoxidation.43b Epoxidation with
azacrown ether-type catalyst 38 was examined by Hori and
co-workers, and up to 83% ee was obtained for 1,3-diaryl
enones using H2O2 (Figure 23).44 The alkyl groups on the
Figure 20. Guanidinium salt catalysts 31−35. nitrogen were shown to have a significant effect on the
epoxidation. The aliphatic ether oxygen was involved in the
catalyst, giving chalcone epoxide in 99% yield and 93% ee complexation with the cation and was also crucial for the
(Figure 21).39 Epoxidation using cyclic guanidinium salts 32 epoxidation. Replacement of this oxygen with a methylene
group led to a dramatic decrease of the enantioselectivity.44
2.2. Peptide-Type Catalysts
2.2.1. Polypeptide-Catalyzed Epoxidation under Tri-
phasic Conditions. In 1980, Juliá and co-workers reported a
polypeptide-catalyzed asymmetric epoxidation45 of (E)-chal-
cone with H2O2−NaOH in toluene−water.46 The reaction
system was triphasic due to the insolubility of the polypeptide
catalyst in toluene and water. Chalcone epoxide was obtained in
85% yield and 93% ee with poly-L-alanine (41a) at room
temperature for 24 h (Scheme 7, Figure 24). The catalyst could
be recovered and reused but gave substantially reduced yield
and ee for the epoxide. Much lower yields and ee’s were
obtained with poly-L-glutamate catalysts 42 and 43 (Scheme 7,
Figure 21. Epoxidation of enones with guanidinium salt catalysts.
Scheme 7. Synthesis of Polypeptides 41−43
and 33 was investigated by Nagasawa and co-workers, and up
to 60% ee was obtained for 1,3-diaryl enones (Figure 21).40
Several acyclic guanidinium salts such as 34 and 35 were
subsequently studied for the epoxidation by the same group
(Figure 20).41,42 Bifunctional urea−guanidinium salt 35 was
shown to be an effective catalyst, giving the epoxidation
products of various 1,3-diaryl enones in 91−99% yield and 85−
96% ee (Figure 21).42
2.1.4. Crown Ether-Type Catalysts. Crown ether-type
phase-transfer catalysts with attached chiral moieties have also
Scheme 8. Synthesis of Poly-Oxygenated α-

Hydroxydihydrochalcone 46
Scheme 9. Synthesis of Dihydroflavonol 50
Figure 24. Epoxidation of olefins with polypeptide catalysts 41−43.
Figure 24). The polypeptide catalysts can be synthesized via

polymerization of N-carboxyanhydride (NCA) initiated by a
nucleophile such as n-butylamine (Scheme 7). The peptide
length is regulated by the ratio of NCA to initiator. With CLAMPS-poly-L-leucine catalyst 51, chalcones were
Juliá, Colonna, and co-workers subsequently carried out a effectively epoxidized with up to 99% ee under the triphasic
series of studies on the epoxidation, including catalyst structure, conditions (Figure 25). The polymer-supported catalysts could
reaction conditions, and substrate scope, etc.47−50 The degree
of polymerization of the polypeptide catalysts was shown to be
important for the enantioselectivity. For example, the ee
increased from 11% to 96% for epoxidation of (E)-chalcone as
the length of poly-L-alanine increased from n = 5 to 30. The
maximum enantioselectivity was obtained with catalyst 41c
(Scheme 7, Figure 24).47 A variety of polypeptides derived
from different amino acids were also extensively studied.49
Comparable results (88−95% ee) were achieved for (E)-
chalcone with poly-L-leucine and poly-L-isoleucine. These
catalysts are more stable than poly-L-alanine under the reaction
conditions since they are more sterically hindered and thus less Figure 25. Epoxidation of chalcones with polypeptide catalyst 51.
prone to hydrolysis, which is beneficial for the recycle of the
catalyst. The copolymer catalyst derived from L-alanine and L- be recovered and reused several times without substantial loss
leucine gave 95% ee for (E)-chalcone.49 Studies showed that of catalytic activity.53 Flisak, Lantos, and co-workers showed
polypeptides with carboxyl and ester groups at the C-terminus that chalcone epoxides could be converted to the correspond-
were also effective catalysts for epoxidation.50 A cross-linked ing glycidic esters in good yields via Baeyer−Villiger oxidation
polystyrene-supported poly-L-alanine gave 82% yield and 84% (Scheme 10).54 The substituent on the phenyl group was
ee for epoxidation of (E)-chalcone.50 Reaction conditions were
also investigated with (E)-chalcone as substrate and 41a as Scheme 10. Synthesis of Glycidic Esters via Epoxidation and
catalyst, and optimal results were obtained with H2O2−NaOH Baeyer−Villiger Oxidation
in toluene or CCl4.47 The epoxidation was further extended to
other electron-deficient olefins with catalyst 41a, although
lower ee’s were obtained as compared to (E)-chalcone (Figure
24).47,48
Ferreira, Bezuidenhoudt, van Rensburg, and co-workers
investigated the asymmetric epoxidation of poly-oxygenated
chalcones with the triphasic system and the transformations of
the resulting chalcone epoxides.51 For example, chalcone 44
was epoxidized with poly-L-alanine and H2O2−NaOH in CCl4
to give epoxide 45 in 74% yield and 84% ee,51b which was
hydrogenated to α-hydroxydihydrochalcone 46 in 88% yield
and 76% ee (Scheme 8).51c,52 Optically active dihydroflavonol important for the regioselectivity of the Baeyer−Villiger
50 could be synthesized in 83% ee from epoxide 48 via epoxide oxidation. Chalcone epoxides and glycidic esters could be
ring opening with phenylmethanethiol and subsequent made on a multihundred gram scale using this process.54
cyclization (Scheme 9).51d,e Lantos, Novack, and co-workers reported the synthesis of
In 1990, Itsuno and co-workers reported the epoxidation of SK&F 104353 (55) (a potent leukotriene antagonist) via
chalcones using poly-L-alanine and poly-L-leucine immobilized asymmetric epoxidation, Baeyer−Villiger oxidation, and further
on cross-linked aminomethyl polystyrene (CLAMPS) resin.53 transformations (Scheme 11).55 The poly-L-leucine catalyst was
synthesized using freshly prepared leucine-NCA in a humidity Scheme 12. Epoxidation of Enone 56 and Subsequent Cross
chamber with 70−75% relative humidity.55 Couplings
Scheme 11. Synthesis of SK&F 104353 (55)
and catalyst loading.59 The modified epoxidation process was

During 1995−1996, Roberts and co-workers reported on applied to several enones and an alkenyl sulfone59c,e with one
their efforts to expand the scope of the poly-L-leucine-catalyzed example being carried out on 100 g scale59d,e (Figure 27). In
asymmetric epoxidation under various reaction conditions.56
High ee’s (up to >99%) were achieved for a variety of α,β-
unsaturated ketones including heterocyclic enones, alkyl- or
alkynyl-substituted enones, dienones, dienediones, and ene-
diones (Figure 26). Along with H2O2, sodium perborate and
sodium percarbonate (Na2CO3·1.5H2O2) were also found to be
suitable oxidants for the epoxidation.56,57
Figure 27. Epoxidation of olefins with polypeptide catalyst under PTC

conditions.
2004, Roberts and co-workers reported their studies on the

epoxidation of enones and arylvinyl sulfones using poly-L-
leucine as catalyst and Bu4NHSO4 (Figure 28).60 Epoxidation
using poly-L-leucine immobilized on hydrotalcite and TBAB
under triphasic conditions was also reported by Segarra and co-
workers.61
Figure 26. Epoxidation of various electron-deficient olefins with

polypeptide catalysts.
As shown by Falck and co-workers in 1997, stannyl-

substituted enone 56 was an effective substrate for the
asymmetric epoxidation, giving stannylepoxide 57 in 90% Figure 28. Epoxidation of olefins with polypeptide catalyst under PTC
yield and >99% ee with poly-L-leucine as catalyst (Scheme conditions.
12).58 The epoxide was converted into epoxy ketones 58 and
59 by Cu2 S-mediated thiocarboxylation and allylation, 2.2.2. Polypeptide-Catalyzed Epoxidation under Bi-
respectively (Scheme 12). phasic Conditions. In 1997, Roberts and co-workers
In 2003, Geller, Militzer, and co-workers reported that developed a highly effective biphasic nonaqueous system for
addition of phase-transfer catalysts (PTCs), such as tetrabuty- the polypeptide-catalyzed asymmetric epoxidation.62 Aqueous
lammonium bromide (TBAB), as cocatalyst to the triphasic H2O2 and NaOH were replaced with urea−H2O2 (UHP) and
system largely accelerated the polypeptide-catalyzed epoxida- 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), respectively, which
tion, thus leading to significant reduction of the reaction time required no aqueous phase. Under biphasic conditions, enones
were efficiently epoxidized with immobilized poly-L-leucine and could be recycled. Tang and co-workers reported that poly-
(CLAMPS-PLL) as catalyst in THF to give the corresponding L-leucine could be covalently linked to silica, and the resulting
epoxides with up to >95% ee (Figure 29, Method A). catalyst (60) was highly effective for the epoxidation, giving up
to 97% ee for (E)-chalcone (Figure 30).68
Figure 30. Epoxidation of chalcones with silica-grafted poly-L-leucine.
The synthetic applications of the epoxidation using silica-

absorbed and other solid-supported polypeptide catalysts were
extensively investigated by Roberts and co-workers. For
example, 2′-aminochalcone epoxide (62) was converted to
tetrahydroquinolone 63 in 64% yield via an intramolecular
nucleophilic ring opening (Scheme 13).64d 3-Acetamido-1,2-
Scheme 13. Synthesis of Tetrahydroquinolone 63
diol 67 was obtained from epoxy ketone 65 via oxime

formation, concomitant epoxide ring opening, reduction, and
Figure 29. Epoxidation of olefins with polypeptide catalysts under acetylation (Scheme 14).67h As shown in Schemes 15 and 16,
biphasic conditions.
Scheme 14. Synthesis of 3-Acetamido-1,2-diol 67
DABCO−1.5H2O2 was also found to be an effective oxidant
(Figure 29, Method B).62 This biphasic system greatly reduced
the reaction time. The reaction avoided use of aqueous NaOH,
which allowed the epoxidation to be extended to alkali-sensitive
substrates and eliminated the degradation of the polypeptide
catalyst caused by NaOH.62 Roberts and co-workers showed
that the epoxidation also proceeded effectively with sodium
percarbonate (Na2CO3·1.5H2O2) in a miscible solvent mixture
such as DME/H2O, giving the epoxides in up to 96% ee
(Figure 29, Method C).63 In this case, sodium percarbonate
was thought to act as an oxidant as well as a base. The substrate
scope for the biphasic system was also investigated by Roberts nucleophilic addition of Grignard reagents to epoxy ketones 69
and co-workers. A variety of α,β-unsaturated ketones including and 74 proceeded diastereoselectively to give epoxy tertiary
chalcones, alkyl-substituted enones, dienones, trienones, and alcohols 70 and 75, respectively. Treatment of 70 with TBSCl
trisubstituted enones bearing an exocyclic CC bond were and imidazole provided epoxy alcohol 71 in 69% yield via a
epoxidized with high ee’s (Figure 29).64 Wang and co-workers Payne rearrangement. Epoxide 70 was opened by SnCl4 to give
reported the epoxidation of chalcones (up to 95% ee) with 1-chloro-2,3-diol 72 in 86% yield with retention of config-
poly-L-leucine using H2O2 and NH4HCO3.65 uration at the benzylic carbon (Scheme 15). SnCl4 likely
Roberts and co-workers also extensively studied the coordinated to the epoxide oxygen and delivered the chloride
epoxidation with the polypeptide catalyst immobilized on a anion to the benzylic carbon intramolecularly.69 Epoxy tertiary
poly(ethylene glycol) (PEG) polystyrene support66 and alcohol 75 was converted into β-hydroxy ketone 76 with
absorbed on silica67 under biphasic conditions (Figure 29, Yb(OTf)3 via pinacol-type rearrangement (Scheme 16).67e,f
Method E).67d,e High ee’s were obtained for various enones Galactonic acid derivative 79 (Scheme 17)70 and naturally
with these catalysts. The readily prepared silica-absorbed occurring styryl lactones such as (+)-goniopypyrone (84) and
catalyst was highly active, robust, and operationally simple (+)-goniofufurone (85) (Scheme 18)71 were synthesized from
Scheme 15. Synthesis of α,β-Epoxy Alcohol 71 and Halodiol diltiazem hydrochloride (91) (a potent blood-pressure-low-
72 ering agent) (Scheme 20),64a (+)-clausenamide (94) (an
Scheme 20. Synthesis of Diltiazem Hydrochloride (91)
antiamnaesic agent with potent hepatoprotective activity)

(Scheme 21),66 and anti-inflammatory agents such as (S)-
Scheme 16. Synthesis of β-Hydroxy Ketone 76
fenoprofen (97)67b,d and (S)-naproxen (100) (Scheme 22).67d
Scheme 21. Synthesis of (+)-Clausenamide (94)
Scheme 17. Synthesis of Galactonic Acid Derivative 79
Scheme 22. Synthesis of (S)-Fenoprofen (97) and (S)-

Naproxen (100)
Scheme 18. Synthesis of (+)-Goniopypyrone (84) and

(+)-Goniofufurone (85)
Imidazolium-attached polypeptides have also been inves-

tigated for epoxidation. In 2009, Tang, Yang, and co-workers
reported that imidazolium-modified poly-L-leucines 101 were
highly enantioselective catalysts for epoxidation, providing
chalcone epoxides in up to 99% ee (Figure 31).72 A one-pot
protocol consisting of Claisen−Schmidt condensation and
corresponding epoxy ketones 78 and 81 by Roberts and co- asymmetric epoxidation with imidazolium-modified poly-L-
workers. The epoxy ketones were also elaborated to several leucine 101a was also reported by the same group.73 In 2012,
pharmaceuticals, including Taxol side chain 86 (Scheme 19),64a Bhagat and co-workers showed that epoxidation of acyclic and
cyclic enones could be achieved with imidazolium-based
Scheme 19. Synthesis of Taxol Side Chain 86 asparagine catalyst 102 using H2O2 as the oxidant in DMF,
giving the epoxides in 80−90% ee (Figure 32).74
2.2.3. Polypeptide-Catalyzed Epoxidation under Ho-
mogeneous Conditions. Polypeptide catalysts soluble in
organic solvents have also been investigated for epoxidation. In
2000, Ohkata and co-workers reported the epoxidation of (E)-
chalcone with several soluble oligopeptides containing α-
Figure 31. Epoxidation of chalcones with imidazolium-modified poly-

L-leucines.
Figure 33. Epoxidation of chalcone with soluble peptide catalysts.
reactor. After the epoxide and unreacted chalcone were passed

through the nanofiltration membrane, the catalyst was retained
on the membrane and reused for epoxidation.
2.2.4. Epoxidation with Peptides Containing Unnatu-
ral Amino Acids. Polypeptides containing unnatural amino
acids have also been explored for epoxidation. In 2001, Roberts
and co-workers showed that poly-β-leucine was a viable
epoxidation catalyst, giving the chalcone epoxide in 92%
conversion and 70% ee.79 In 2010, Tanaka and co-workers
reported the epoxidation of enones with peptide catalysts
containing cyclic α,α-disubstituted amino acids. A variety of
enones, including alkyl-substituted enones, were efficiently
Figure 32. Epoxidation of enones with imidazolium-based asparagine epoxidized in 96−98% ee with catalyst 106 and urea−H2O2 in
catalyst. THF (Figure 34).80 Introduction of the cyclic α,α-disubstituted
aminoisobutyric acid (Aib) using urea−H2O2 and DBU in

THF.75 The epoxide was obtained in 73% yield and 94% ee
with catalyst 103 (Scheme 23). The Aib residue likely
Scheme 23. Epoxidation of Chalcone with Soluble Peptide

Catalyst
Figure 34. Epoxidation of enones with peptide catalyst 106.
promoted formation of a helical structure as well as enhanced

the solubility of the peptides in organic solvents. In 2001, amino acid could stabilize the α-helical structure, which was
Roberts and co-workers prepared diaminopoly(ethylene thought to be important for asymmetric induction. Epoxidation
glycol)-bound poly-L-leucine catalysts 104a−d and examined with cyclic peptides 107, containing α-aminoisobutyric acid (a
the epoxidation of (E)-chalcone with these catalysts using helical promoter), was reported by Demizu, Kurihara, and co-
urea−H2O2 and DBU in THF (Figure 33).76,77 Under the workers in 2011 (Figure 35).81 Catalyst 107b, with a longer
homogeneous conditions, the chalcone epoxide was obtained side chain at the 3 and 7 positions, gave higher
with 58−80% conversion and 95−98% ee. Polymer enlarged enantioselectivity than 107a for epoxidation of (E)-chalcone.
poly-L-leucine 104e gave higher conversion (>99%) for Up to 99% ee was obtained for epoxy ketones with catalyst
epoxidation of (E)-chalcone as reported by Tsogoeva and co- 107b and urea−H2O2. Kudo and Akagawa incorporated 3-(1-
workers (Figure 33).78 They also showed that styrene/ pyrenyl)alanine [Ala(1-Pyn)] into resin-supported polypeptide
aminomethylstyrene-copolymer-linked poly-L-leucine 105 was 108 (Figure 36).82 Various α,β-unsaturated aldehydes were
a highly effective catalyst for epoxidation of (E)-chalcone epoxidized with catalyst 108 and H2O2, giving epoxy alcohols in
(Figure 33).78 The epoxidation was carried out in a membrane up to 95% ee upon reduction with NaBH4.
Scheme 24. Epoxidation of Chalcone with Catalyst 109 or

110
with the N-terminal amidic N−H groups. The helical

conformation and hydrogen-bonding motif are likely determin-
ing factors for the stereocontrol of the epoxidation.86 Kelly,
Figure 35. Epoxidation of enones with oligopeptide catalyst 107.
Roberts, and co-workers have shown that the conjugate
addition of HOO− to olefin, the first step in the epoxidation,
is reversible.87 In their mechanistic studies, Colonna, Ottolina,
and co-workers observed saturation kinetics for both chalcone
and HOO¯ in the epoxidation of chalcone with PEG-bound
poly-L-leucine catalyst.88,45e This is consistent with a steady-
state random bireactant system, in which both chalcone and
HOO− must bind to the catalyst to form the PLL·HOO−·
chalcone complex before reaction occurs (Scheme 25).
Scheme 25
Figure 36. Epoxidation of enals with polypeptide catalyst 108.
Pathway I was shown to be kinetically favored over pathway

2.2.5. Mechanistic Insights. In their initial reports, Juliá
II.88 Further kinetic studies with calorimetry by Blackmond and
and Colonna indicated that an α-helical structure of
co-workers indicated that the epoxidation proceeded via
polypeptide catalysts might be important for asymmetric
pathway I, with pathway II being kinetically negligible.89
induction.47,50 They also suggested that the hydrogen bonding
between the peptide and chalcone be involved for stereocontrol 2.3. Chiral Bifunctional Base-Catalyzed Epoxidation
as a racemic epoxide was obtained when the epoxidation of 2.3.1. Chiral Guanidines. Various chiral bifunctional bases
chalcone was carried out in methanol, which likely disrupted such as guanidines and amino alcohols have been developed for
the hydrogen bonding.49 The importance of α-helical structure asymmetric epoxidation of electron-deficient olefins. Taylor and
on the enantioselectivity of the epoxidation has been further co-workers studied a number of chiral guanidines such as 111−
demonstrated by Ohkata,75,83 Berkessel,84 Kelly,77 Tanaka,80 115 (Figure 37) for epoxidation of quinone 124, and up to 60%
Demizu, Kurihara,81 and others. Studies indicated that the ee was obtained with 114 and TBHP (Scheme 26).90 A series
amino acid residues at the N-terminus of the peptide catalysts of 5-membered ring (116−120)91 and binaphthyl-based
appeared to be responsible for the stereochemistry and guanidines (121−123)92 were also investigated by the groups
enantioselectivity of the epoxidation.76,84,85 Roberts and co- of Ishikawa and Terada, respectively (Figure 37). Up to 70% ee
workers showed that high ee’s (91−92%) were obtained for was obtained for epoxidation of (E)-chalcone (Figure 38).91b It
epoxidation of chalcone with catalysts 109 containing five or six is likely that the guanidine acts as a base to deprotonate the
85c
L-Leu residues at the N-terminus (Scheme 24). In their oxidant, and the NH group forms the hydrogen bond with the
studies, Berkessel and co-workers demonstrated that the enone and/or the oxidant during the reaction (Figure 39).91a
enantioselectivity reached the maximum (96−98%) with a 2.3.2. Chiral β-Amino Alcohols. A class of amino alcohols
TentaGel S supported catalyst 110 containing only five L-Leu as outlined in Figure 40 has also been shown to be effective
residues (Scheme 24).84a These five residues allowed formation bifunctional catalysts for epoxidation of electron-deficient
of one helical turn, which provided the basic structural unit olefins.93 In 2005, Lattanzi reported that readily available α,α-
required for high enantioselectivity. Molecular modeling studies diphenyl-L-prolinol (125a) could act as the catalyst for
suggested that chalcone be bound to the α-helix via hydrogen epoxidation of enones with TBHP, giving up to 80% ee for
bonding between the carbonyl group and the NH groups of the chalcones (Figure 41).94 The reaction mechanism was
catalyst. The stereochemical outcome of the epoxidation was proposed as outlined in Scheme 27. In this reaction, the
proposed to be determined by the helical chirality.84a amino alcohol acted as a bifunctional catalyst. TBHP was
A reaction model was also proposed by Kelly and Roberts.86a deprotonated by the amine of the catalyst to form a tight ion
The α helix binds to H2O2 and chalcone via hydrogen bonding pair. The hydroxyl group of the catalyst was thought to
Figure 40. β-Amino alcohol catalysts.

Figure 37. Guanidine catalysts.
Scheme 26. Epoxidation of Quinone 124 Using Guanidine

Catalysts 111−115
Figure 41. Epoxidation of enones with amino alcohol catalysts 125−

131.
Scheme 27. Proposed Mechanism for Epoxidation of Enones

with Catalyst 125a
Figure 38. Epoxidation of enones with guanidine catalysts 116−123.
and co-workers subsequently showed that the reactivity and

enantioselectivity could be further improved with substituted
phenyl catalysts, and over 90% ee was obtained with 125b and
Figure 39. Proposed transition state for guanidine 116-catalyzed 125c for some chalcones (Figures 40 and 41).96 Epoxidation of
epoxidation with TBHP. chalcones using dinaphthyl-L-prolinol catalyst 125e was also
reported by Liu and co-workers, and up to 85% ee was obtained
(Figures 40 and 41).97 Zhao, Zhu, and co-workers demon-
coordinate with the enone via hydrogen bonding to activate the strated that dendritic and fluorous diaryl-L-prolinol catalysts
double bond and direct addition of the peroxide anion such as 125f and 125g were effective for epoxidation of enones
stereoselectively.93d,94,95 This noncovalent activation mecha- and could be recycled with little loss of activity and
nism through hydrogen-bonding interactions was also enantioselectivity.98 In 2007, Zhao and co-workers also
supported by DFT calculations.95 An alternative activation reported their studies on the epoxidation with 4-substituted
mode via formation of an iminium ion between the enone and α,α-diarylprolinols such as 126 (Figure 40). A variety of
the prolinol catalyst was believed to be less plausible. Lattanzi substituted chalcones were epoxidized in 89−96% ee (Figure
41).99 Besides prolinols, various other types of amino alcohols Scheme 28. Synthesis of (−)-Norbalasubramide (135a) and
have also been examined. In their further studies, Lattanzi and (−)-Balasubramide (135b)
co-workers showed that four- and six-membered ring catalysts
127 and 128 were less effective than corresponding prolinol
catalyst 125b (Figures 40 and 41).100 Amino alcohol 129 with
azabicyclo[2.2.1]heptane skeleton was synthesized and inves-
tigated for epoxidation by Loh and co-workers (Figure 40).101
Up to 88% ee was obtained for α,β-unsaturated ketones (Figure
41). Epoxidation using acyclic amino alcohol catalysts such as
130102 and 131100 was reported by Liu, Zhang, Lattanzi, and
co-workers (Figures 40 and 41). Up to 70% ee was obtained for
epoxidation of chalcones.102
Epoxidation with α,α-diarylprolinols has been extended to Scheme 29. Epoxidation of α-Ylideneoxindoles with
various other electron-deficient olefins. For example, Lattanzi Diarylprolinol Catalyst 125a
and co-workers showed that 2-arylidene-1,3-diketones103 and
trisubstituted acrylonitriles104 could be epoxidized with
catalysts 125d and 125c, giving the corresponding epoxides
in up to 85% ee (Figure 42). As shown by Zhao and co-
2.3.3. Cinchona Alkaloid-Derived Thioureas. Cinchona

alkaloids and their derivatives have also been investigated for
asymmetric epoxidation. Recently, Lattanzi and co-workers
reported that 1,1-dicarbonyl terminal olefins were enantiose-
lectively epoxidized with cinchona thiourea catalyst 136 and
TBHP to give terminal epoxides in up to 99% ee (Figure
44).107 The epoxide product contains a quaternary stereogenic
center and can be opened by nucleophiles such as azide to form
chiral alcohols (Scheme 30).107
Figure 42. Epoxidation with diarylprolinol catalysts 125c and 125d.
workers, a variety of β,γ-unsaturated α-keto esters and α,β-

unsaturated trichloromethyl and trifluoromethyl ketones were
epoxidized using catalysts 125c and 126 in up to 99% ee
(Figure 43).105 Chiral epoxide 132 was readily converted to
(−)-norbalasubramide (135a) and (−)-balasubramide (135b)
(Scheme 28).105 Gasperi and co-workers also extended the
epoxidation to α-ylideneoxindoles using catalyst 125a to give
the corresponding epoxides with up to 88% ee (Scheme 29).106
Figure 44. Epoxidation with cinchona thiourea catalyst 136.
Scheme 30. Transformation of the Terminal Epoxide
Figure 43. Epoxidation with diarylprolinol catalysts 125c and 126.

2.4. Epoxidation via Iminium/Enamine Catalysis

2.4.1. Pyrrolidine-Based Catalysts. In contrast to α,β-
unsaturated ketones, little had been reported previously for
asymmetric epoxidation of α,β-unsaturated aldehydes. In 2005,
Jørgensen and co-workers reported a highly enantioselective
epoxidation process for α,β-unsaturated aldehydes using
diarylprolinol silyl ether catalyst 137 and H2O2, giving the
corresponding epoxides in high yields with high dr values
(≥90:10) and ee’s (up to 98% ee) (Figure 45).108 The authors
Figure 46. Pyrrolidine-based chiral amine catalysts 138−145.
Various α,β-unsaturated aldehydes were epoxidized using 144

as catalyst (10 mol %) and H2O2 or sodium percarbonate as
oxidant with up to 98% ee (Figure 47).111 With a one-pot
epoxidation/reduction/ring-opening sequence, 1,2,3-triols were
synthesized from α,β-unsaturated aldehydes in up to 98% ee
(Figure 48).112
Figure 45. Epoxidation of α,β-unsaturated aldehydes with catalyst 137.
also showed that the epoxidation could be carried out in a

benign solvent such as EtOH−H2O (3:1).109 A mechanistic
proposal for the epoxidation is shown in Scheme 31. The chiral
Scheme 31. Proposed Mechanism for Epoxidation of Enals

with Pyrrolidine-Based Catalysts
Figure 47. Epoxidation of α,β-unsaturated aldehydes with catalysts

138−145.
amine catalyst initially reacts with the α,β-unsaturated aldehyde Figure 48. One-pot synthesis of 1,2,3-triols via asymmetric
to generate an iminium salt intermediate to which H2O2 epoxidation.
nucleophilically adds at the β-carbon to form an enamine
intermediate. Upon ring closure and subsequent hydrolysis of In 2012, Corrêa, Paixão, and co-workers demonstrated that a
the epoxy iminium ion, the chiral epoxide is formed with modified class of prolinol silyl ethers, such as 146, efficiently
regeneration of the amine catalyst.108 In a subsequent epoxidized α,β-unsaturated aldehydes using H2O2 in EtOH−
computational study,110 Santos and co-workers indicated that H2O (3:1), giving the epoxy aldehydes in up to 99:1 dr and
besides being an oxidant, H2O2 could act as a cocatalyst to 99% ee (Figure 49).113 A tandem asymmetric epoxidation/
promote initial formation of the iminium ion intermediate, and Passerini reaction was also reported with catalyst 146 (Figure
a hydroxyl ion was likely involved in the epoxidation. 50).113,114
In 2006, Córdova and co-workers reported their studies on α-Substituted acroleins could be epoxidized with diphenyl-
the epoxidation of α,β-unsaturated aldehydes with a series of prolinol silyl ether catalyst 147 and H2O2 to give the terminal
pyrrolidine-based catalysts such as 138−145 (Figure 46). epoxides in up to 94% ee as demonstrated in 2010 by Hayashi
Figure 49. Epoxidation of α,β-unsaturated aldehydes with catalyst 146.
Figure 52. Epoxidation of enals with catalysts 148−150.
Asymmetric epoxidation of enals with diarylprolinol silyl

ether catalysts has been applied to the synthesis of a number of
building blocks, natural products, and bioactive molecules. In a
series of studies, Jørgensen and co-workers developed various
one-pot synthetic processes incorporating their epoxidation
Figure 50. Tandem asymmetric epoxidation/Passerini reaction. method108 and other transformations,117 providing access to a
variety of synthetically useful molecules, such as isoxazoline-N-
and co-workers (Figure 51).115 The epoxy aldehyde was readily oxides (152),117a propargylic epoxides (153),117b acetal-
converted to the corresponding epoxy ester via oxidation with protected trans-2,3-dihydroxyaldehydes (154),117c β-hydroxy
esters (155),117d substituted furans (156),117e imidazo[1,2-
a]pyridines (157),117f 1,3-azoles (158),117g 2,3-dihydrobenzo-
furans (159),117h and substituted thiophenes (160)117i
(Scheme 32).
In the syntheses of (−)-aspinolide A (163) and (+)-stago-
nolide C (166) reported by Suryavanshi, Sudalai, and co-
Scheme 32. One-Pot Syntheses of Various Building Blocks

via Asymmetric Epoxidation
Figure 51. Epoxidation of α-substituted acroleins with catalyst 147.
NaClO2 and esterification with TMSCHN2, as illustrated in the

synthesis of (R)-methyl palmoxirate (a potent oral hypoglyce-
mic and antiketogenic agent).115
A series of β-fluorinated pyrrolidines was investigated for
epoxidation of enals by Gilmour and co-workers. Among them,
(S)-2-(fluorodiphenylmethyl)pyrrolidine (150) was found to
be a highly effective catalyst, giving epoxides with up to 98% ee
(Figure 52).116 The higher ee obtained using 150, as compared
to nonfluorinated catalyst 149, could be attributed to the
fluorine−iminium ion gauche effect, which allowed the iminium
ion (151) to adopt a conformation more favorable for
asymmetric induction.116
workers, epoxy alcohols 162 and 165 were obtained in 99% ee Carreira and co-workers employed catalyst 144 for
from the corresponding enals via epoxidation with catalyst 137 epoxidation of enal 184 in the synthesis of epoxyisoprostanes
and subsequent reduction with NaBH4 (Scheme 33).118 such as EC (187) and PECPC (188) (Scheme 37).122 Epoxy
Scheme 33. Syntheses of (−)-Aspinolide A (163) and Scheme 37. Synthesis of Epoxyisoprostanes
(+)-Stagonolide C (166)
In their total synthesis of hirsutellone B (171), Nicolaou and aldehyde 185 was converted to EC by aldol condensation with
co-workers reported that epoxy ester 168 could be synthesized cyclopentenone 186 and subsequent enzymatic hydrolysis.
from aldehyde 167 in 58% overall yield over three steps using PECPC was obtained by the coupling of EC with lyso-PC
144 as the epoxidation catalyst. Epoxy ester 168 was under Yamaguchi’s conditions. Xuan, Yan, and co-workers
subsequently transformed into hirsutellone B (171) (Scheme reported a one-pot epoxidation of trans-cinnamaldehydes with
34).119 Kuwahara and co-workers showed that epoxide 173 was catalyst 189 and oxidative esterification with NBS in CH3OH,
giving α,β-epoxy esters in 54−73% yield and 93−99% ee
Scheme 34. Synthesis of Hirsutellone B (171) (Scheme 38).123 Epoxide 190 was utilized to synthesize
(−)-clausenamide (ent-94) (Scheme 38).123
Scheme 38. Synthesis of (−)-Clausenamide (ent-94)
readily converted to lactone 175 via olefination and cyclization

(Scheme 35).120 Lactone 175 was further elaborated to
Scheme 35. Syntheses of Bacilosarcins A (176) and B (177)
2.4.2. Chiral Amine Salt Catalysts. Various chiral amine

salt catalysts were investigated for epoxidation of α,β-
unsaturated aldehydes and ketones. In 2006, MacMillan and
co-workers reported that a variety of enals were effectively
epoxidized with imidazolidinone salt catalyst 194 in the
bacilosarcins A (176) and B (177). This epoxidation/ presence of iminoiodinane PhINNs and AcOH, giving the
olefination/cyclization sequence was also employed in their corresponding epoxides in 72−95% yield and 85−97% ee
total syntheses of jaspines A and B (Scheme 36).121 (Figure 53).124 The epoxidation was proposed to proceed via
an iminium/enamine pathway as shown in Scheme 39. The
Scheme 36. Syntheses of Jaspines B (182) and A (183) choice of oxidant was found to be very important for the
reaction efficiency and enantioselectivity, and PhINNs gave
the best results overall. Studies showed that PhIO was slowly
released in situ from PhINNs under mild acidic conditions
and acted as the actual oxidant (Scheme 39).124
In 2008, List and co-workers reported a counteranion-
directed asymmetric epoxidation of enals with amine salts
bearing chiral phosphates as catalysts.125 Among various
catalysts examined, amine salt 198 gave the best results for
the epoxidation. With this catalyst, a variety of 1,2-disubstituted
Scheme 40. Catalytic Pathway for Epoxidation of Enals with

Chiral Amine Salts
Figure 53. Epoxidation of enals with catalyst 194.
Scheme 39. Proposed Mechanism for Epoxidation of Enals

with Imidazolidinone Salt
and β,β-disubstituted enals were efficiently epoxidized in 60−

95% yield and up to 96% ee using TBHP as oxidant (Figure
54).125 In this case, asymmetric induction was controlled by the
Figure 55. Epoxidation of enals with catalysts 199a and 199b.
In 2010, Luo, Cheng, and co-workers reported that

asymmetric epoxidation of α-substituted acroleins could be
realized with simple chiral primary−tertiary diamine-based
amine salt catalysts bearing achiral counteranions such as 200,
giving epoxy alcohols in up to 88% ee upon reduction with
NaBH4 (Figure 56).127
Cyclic enones had been challenging substrates for previously
reported asymmetric epoxidation methods. In 2008, List and
co-workers reported that a variety of cyclic enones were
Figure 54. Epoxidation of enals with chiral amine salt catalysts 195−
198.
chiral phosphate counteranion (Scheme 40). In their further

studies, List and co-workers demonstrated that asymmetric
epoxidation of α-branched enals could also be achieved with a
catalyst consisting of a quinine-derived amine and a chiral
phosphoric acid such as 199a and 199b, giving the epoxides in
up to 98% ee with H2O2 (Figure 55).126 Figure 56. Epoxidation of enals with catalyst 200.

efficiently epoxidized using catalysts containing a chiral diamine

and a chiral or achiral acid, such as 201−203, giving the epoxy
ketones in up to 99% ee (Figure 57).128,126b The primary amine
Figure 58. Epoxidation and peroxidation of acyclic enones with

catalysts 202 and 204.
Figure 59. Hydroperoxidation and epoxidation of acyclic enones.
Figure 57. Epoxidation of cyclic enones with catalysts 201−203. catalyst 206, epoxy ketones were obtained in up to 84% ee
using TBHP (Figure 60).132 In 2011, Zhao, Zou, and co-
of the catalyst activates the enone by formation of an iminium
ion and the tertiary amine acts as a general base to promote the
conjugate addition of H2O2 to the iminium ion (Scheme
41).128,126b,129
Scheme 41. Catalytic Pathway for the Amine Salt-Catalyzed

Epoxidation of Cyclic Enones
Figure 60. Epoxidation of chalcones with catalyst 206.
workers demonstrated that primary−secondary diamine salts

were effective catalysts for epoxidation of enones, providing
epoxides in 68−87% yield and up to 99% ee with amine salt
207 in the presence of cumene hydroperoxide (Figure 61).133
Presumably, the primary amine moiety activates the enone, and
the secondary amine activates the oxidant (Figure 61).
In 2008, Deng and co-workers reported that epoxy ketones
In 2010, Jørgensen and co-workers reported that optically
were predominantly formed in up to 97% ee when acyclic
active allyic alcohols could be synthesized from enones via a
aliphatic enones reacted with cumene hydroperoxide in the
one-pot epoxidation/Wharton reaction sequence.134 With
presence of chiral amine salt catalyst 202 at 23−55 °C (Figure
amine salt catalyst 202 and H2O2, various enones were
58).130 However, β-peroxy ketones were obtained as major
transformed into allylic alcohols in 87−99% ee (Figure 62).
products in high ee’s when the reaction was carried out with
In 2011, Tu, Cao, and co-workers demonstrated that
catalyst 204 at lower temperature (0−23 °C) (Figure 58).130 In
spirocycloalkanediones could be synthesized in 93−99% ee
their studies, List and co-workers found that cyclic
from the corresponding cyclic enones by a one-pot
peroxyhemiketals could be obtained in up to 95% ee from
epoxidation/semipinacol rearrangement process with amine
acyclic aliphatic enones with catalyst 205 and H2O2 (Figure
salt 202 as catalyst and H2O2 as oxidant for the epoxidation
59).131,126b Epoxy ketones could also be obtained in 55−90%
(Figure 63).135
yield and 90−99% ee via a one-pot process involving reacting
enones with H2O2 in the presence of catalyst 202 and basic 2.5. Chiral Ketone-Catalyzed Epoxidation
work up with 1 N NaOH (Figure 59).131,126b 2.5.1. Methodology Development. Dioxiranes are highly
Zhang and co-workers investigated the structural effect of the effective species for epoxidation of olefins. A chiral dioxirane
catalyst on the epoxidation of chalcones. With amine salt can be generated in situ from a chiral ketone and an oxidant
Scheme 42. Catalytic Cycle for the Chiral Ketone-Catalyzed

Epoxidation of Olefins
Figure 61. Epoxidation of enones with catalyst 207. 64) and up to 12.5% ee was obtained for trans-β-
methylstyrene.137a In their further studies, ketones 217 and
Figure 64. Early examples of chiral ketones for asymmetric

epoxidation.
218 (Figure 64), with electron-withdrawing trifluoromethyl

groups, were shown to be much more active toward
Figure 62. One-pot epoxidation/Wharton reaction sequence.
epoxidation than 215 and 216. Epoxidation with 218 gave
18% and 20% ee for trans-β-methylstyrene and trans-2-octene,
respectively.137b Marples and co-workers investigated the
epoxidation with α-fluorinated 1-tetralones 219 and 1-indanone
220.138 These ketones were found to be active for the
epoxidation, although no ee’s were observed for the resulting
epoxides.
In 1996, Yang and co-workers reported a number of elegant
binaphthyl-based C2-symmetric ketones 221 for epoxidation of
olefins (Figure 65).139 The substituents at the 3 and 3′
positions were found to be important for the enantioselectivity.
Replacing hydrogens with substituents such as Cl, Br, or an
Figure 63. Synthesis of spirocycloalkanediones with catalyst 202. acetal led to higher enantioselectivities (Table 3, entries 1−4).
Para-substituted trans-stilbenes were among the most effective
substrates. The enantioselectivity generally increased with the
such as oxone (2KHSO5·KHSO4·K2SO4) or H2O2 and can be size of the substituent on the stilbene.139 For example, 91% and
converted back to the ketone upon epoxidation of an olefin to 95% ee were achieved for trans-4,4′-diethyl- and trans-4,4′-di-
complete a catalytic cycle (Scheme 42). Significant progress has tert-butylstilbene, respectively, with 10 mol % ketone
been made for the ketone-catalyzed asymmetric epoxidation. A 221d.139b,c Biphenyl-based catalyst 222 provided moderate
variety of structurally diverse ketone catalysts have been selectivity for epoxidation of trans-olefins and trisubstituted
investigated and reported by a number of laboratories. A olefins (Table 3, entry 5).139c Epoxidation of cinnamates with
wide range of olefins, particularly unfunctionalized trans-olefins ketones 221 was extensively investigated by Seki and co-
and trisubstituted olefins, have been effectively epoxidized with workers. Epoxide 236, a key intermediate for diltiazem
high enantioselectivity.136 hydrochloride (91), was obtained in up to 85% ee with catalyst
In 1984, Curci and co-workers reported the asymmetric 221b (Scheme 43).140 Epoxidation with C2-symmetric ether-
epoxidation of olefins with chiral ketones 215 and 216 (Figure linked ketones 223 and 224 was reported by Song and co-
Scheme 43. Synthesis of Diltiazem Key Intermediate 236

Using Ketone 221b
their studies, Behar and co-workers reported that up to 86%

Figure 65. Selected examples of C2-symmetric and related ketones. ee was obtained for epoxidation of trans-β-methylstyrene with
binaphthyl-based α-fluorinated ketone 229 (Table 3, entry
Table 3. Epoxidation of Representative Olefins with C2- 13).144 A number of 1,2-diamine- and 1,2-aminoalcohol-based
Symmetric Ketone Catalysts ketone catalysts were investigated for epoxidation by Tomioka
and co-workers.145 Up to 82% ee was achieved for epoxidation
of 1-phenylcyclohexene with ketones 233 and 234 (Table 3,
entries 18 and 19).145c
Denmark and co-workers reported a series of ammonium
ketones such as 237−242 (Figure 66) for epoxidation (Table
Figure 66. Selected examples of ammonium ketones.
4).136a,143,146,147 The electron-withdrawing ammonium ion

inductively activates the ketone and functions as a phase-
transfer mediator to facilitate the biphasic reaction. Up to 58%
Table 4. Epoxidation of Representative Olefins with

Ammonium Ketone Catalysts
workers in 1997.141 Up to 59% ee was obtained for trans-

stilbene using ketone 224 (Table 3, entry 8). In their studies,
Adam and co-workers showed that up to 81% ee was obtained
for epoxidation of trans-olefins and trisubstituted olefins with
mannitol-derived ketone 225 and tartaric acid-derived ketone
226 (Table 3, entries 9 and 10).142
In 1999 and 2002, Denmark and co-workers reported that α-
fluorinated biphenyl-based 7-membered-ring ketones such as
227 (Figure 65) were highly effective epoxidation catalysts,
giving 94% and 88% ee for trans-stilbene and trans-β-
methylstyrene, respectively (Table 3, entry 11).136a,143 In
ee was obtained for trans-stilbene using 10 mol % α-fluorinated A variety of six-membered carbocyclic ketones have been
tropinone-based ketone 237 (Table 4, entry 1).143,147 investigated for epoxidation. In 1997 and 1999, Shi and co-
In 1998, Armstrong and co-workers reported that α- workers reported a class of quinic acid-derived pseudo-C2-
fluorinated tropinone-based ketone 243a was an effective symmetric ketones with two fused ketals such as 251 (Figure
catalyst for epoxidation, giving 100% conversion and 83% ee for 68), which displayed good reactivity and high selectivity for
phenylstilbene with 10 mol % 243a (Figure 67) (Table 5, entry
Figure 67. Selected examples of bicyclo[3.2.1]octan-3-ones and

related ketones.
Figure 68. Selected examples of six-membered carbocyclic ketones.
Table 5. Epoxidation of Representative Olefins with Ketone
Catalysts 243−250a trans-olefins and trisubstituted olefins.152 trans-Stilbene was
epoxidized in 91% yield and 96% ee with 10 mol % 251b
(Table 6, entry 2).152b Electron-deficient chalcone was also
found to be an effective substrate, giving the epoxy ketone in
85% yield and 96% ee.152b Ketone 252, with one ketal away
from the α position of the carbonyl, displayed significantly
lower reactivity and enantioselectivity as compared to 251,
showing that having the chiral control moiety close to the

Carbocyclic Ketone Catalysts
a
eemax = (100 × product ee/ketone ee).
1).148 Various bicyclo[3.2.1]octan-3-ones and related ketones

were subsequently investigated by Armstrong and co-work-
ers. 149,150 Ketone 246b was found to be the most
enantioselective catalyst, giving 85% conversion and 93%
eemax for stilbene, 71% conversion and 98% eemax for
phenylstilbene, and 89% conversion and 82% eemax for 1-
phenylcyclohexene with 20 mol % catalyst loading (Table 5,
entry 8). In their studies, Klein and Roberts showed that 68%
ee was achieved for stilbene with α-fluorinated 2,4-dimethyl-8-
oxabicyclo[3.2.1]octan-3-one 250 (Table 5, entry 13).151
reacting carbonyl was beneficial for asymmetric induction.153 1-Phenylcyclohexene was epoxidized in 88% yield and 81% ee
Zhao and co-workers also reported their studies on the with 10 mol % ketone 265 (Table 7, entry 2).159 In 2003,
epoxidation with ketone 252 and obtained 85% ee for stilbene Wong and co-workers reported the epoxidation with cyclo-
(Table 6, entry 3).154 dextrin-modified ketone catalyst 266 (Table 7, entry 3).160
In 1998, Yang and co-workers reported the epoxidation of With this ketone, 4-chlorostyrene could be epoxidized in 40%
various substituted stilbenes with α-chlorinated cyclohexanones ee.160 Acetone-bridged cyclodextrins such as 267 (Figure 69)
253 (Figure 68).155 The enantioselectivity was found to be were also synthesized and examined for epoxidation by Bols
significantly influenced by the remote substituent likely due to and co-workers.161
the electrostatic interaction between the polar C−X bond and In 1996, Shi and co-workers reported the discovery of
the phenyl group of the substrate (Table 6, entries 4−8).155 fructose-derived ketone 268 (Figure 70) as a very effective
The enantioselectivity also varied (71.5−88.9% ee) with the chiral inducer for epoxidation of trans-olefins and trisubstituted
substituents on the phenyl groups when various meta- and olefins.162 The ketone was readily prepared from D-fructose by
para-substituted stilbenes were epoxidized with ketone 253b, ketalization and oxidation in two steps.163,164 Its enantiomer
which could be attributed to the n−π electronic repulsion effect was easily prepared from L-fructose, which was made from L-
between the Cl atom of the ketone and the phenyl group of the sorbose.163,165 It was found that the reaction pH had a dramatic
substrate.155 effect on the efficiency of the epoxidation, with pH >10 being
In 2000, Solladié-Cavallo and co-workers reported the optimal.166,163 The epoxidation process with ketone 268
epoxidation of p-methoxycinnamates with α-halogenated (typically 10−30 mol %) has been extended to a wide range
trisubstituted cyclohexanones (Figure 68). Methyl p-methox- of olefins, including aromatic and aliphatic trans-olefins and
ycinnamate was epoxidized in 99% conversion and 40% ee with trisubstituted olefins,163 hydroxyalkenes,167 conjugated di-
30 mol % α-fluoro ketone 254.156a A series of α-fluoro ketones enes,168 enynes,169 silyl enol ethers and enol esters,170,171
including 255−258 was further investigated for epoxidation of vinylsilanes,172 and fluoroolefins173 (Figure 70). The stereo-
olefins (Table 6, entries 9−12),156b−h giving up to 90% ee for chemical outcome of the epoxidation with ketone 268 has been
stilbene using ketone 255 (Table 6, entry 9). highly predictable. The reaction proceeds mainly via spiro
In 2001, Bortolini, Fogagnolo, and co-workers reported that transition state A, with major competition from planar B
up to 75% ee could be obtained for epoxidation of p- (Figure 71). This transition state model was further validated
methylcinnamic acid with keto bile acid 259 (Figure 68).157a and elucidated in the studies on kinetic resolution of
Various keto bile acids and their derivatives were subsequently substituted cyclohexenes and desymmetrization of substituted
investigated for epoxidation of olefins.157b−g p-Methylcinnamic 1,4-cyclohexadienes.174 Further studies showed that the
acid epoxide was obtained in 94% yield and 95% ee with 1 epoxidation also proceeded efficiently with H2O2 as oxidant
equiv of 260.157b Up to 98% ee was achieved for stilbene with in the presence of a nitrile such as CH3CN (Scheme 44),
ketone 263 (Table 6, entry 16).157d providing the enantioselectivity comparable to that of using
Noncyclic chiral ketones have also been studied for oxone.175,176 The peroxyimidic acid resulting from H2O2 and
epoxidation (Figure 69). In 1999, Armstrong and co-workers CH3CN is likely to be the actual oxidant, which reacts with the
ketone to generate the dioxirane.
A series of ketones such as 269−274 (Figure 72) was
synthesized to investigate the structural requirements of the
ketone catalysts for epoxidation.153,177,178 Studies showed that
the dimethyl spiro five-membered ring and the pyranose
oxygen of ketone 268 were important for the reactivity and
enantioselectivity of the epoxidation (Table 8).
Replacement of the fused ketal in 268 with a more electron-
Figure 69. Selected examples of ketones with an attached chiral withdrawing oxazolidinone led to a more robust ketone 275. A
moiety. variety of olefins were epoxidized in good yields and high ee’s
with 1−5 mol % ketone 275 (Figure 73).179 Epoxidation of
reported that up to 34% ee was obtained for epoxidation of 1- electron-deficient α,β-unsaturated esters was achieved in high
phenylcyclohexene with ketone 264 (Table 7, entry 1).158 ee’s with diacetate ketone 276 (Figure 74). High enantiose-
Miller and co-workers prepared a class of peptide-embedded lectivities were also obtained with this ketone for various trans-
trifluoromethyl ketones such as 265 for epoxidation of olefins. olefins and trisubstituted olefins including less reactive enimide
as well as some cis-olefins (Figure 74).180,173,181
Table 7. Epoxidation of Representative Olefins with Ketone In addition to trans-olefins and trisubstituted olefins,
Catalysts 264−266 investigations have also been carried out to develop effective
ketone catalysts for other types of olefins. During such studies,
glucose-derived oxazolidinone ketone 277a (Figure 75) was
found to be highly enantioselective for epoxidation of cis-
olefins.182 To further understand the ketone’s structural effect
on the epoxidation and develop more practical catalysts, readily
prepared N-aryl-substituted oxazolidinone ketones such as
277b and 277c (Figure 75) were designed and found to be
effective catalysts for the epoxidation.183 Epoxidation with
ketone 277 can be extended to a wide variety of olefins,
including aromatic cis-olefins,184,182a,b,183a conjugated cis-
dienes,185 cis-enynes,186,182a,b nonconjugated cis-olefins,187
Figure 71. Spiro and planar transition states for epoxidation with
ketone 268.
Scheme 44. Catalytic Cycle for Epoxidation of Olefins with

H2O2 as Oxidant
Figure 72. Selected examples of carbohydrate-derived ketones and

related ketones.
isomerization observed during the reaction.182a,b,183a,184a,185−187

For conjugated cis-dienes, the epoxidation generally occurred
regioselectively at the cis CC bond.185 When nonconjugated
cis-dec-4-enoic acid (278) was subjected to the epoxidation
conditions, lactone 279 was obtained in 75% yield and 91% ee
Figure 70. Epoxidation of various olefins using ketone 268. (Scheme 45).187 The epoxides obtained from benzylidenecy-
clobutanes can be stereoselectively rearranged to optically
styrenes,188,182b,189 trans-olefins and trisubstituted olefin- active 2-aryl cyclopentanones (Scheme 46).190a It has also been
s,182a,b,190a,c as well as tetrasubstituted benzylidenecyclobuta- shown that epoxidation with ketone 277c can be carried out
nes190b and benzylidenecyclopropanes190c (Figure 75). Epox- using H2O2 as the primary oxidant.191
idation proceeds in a stereospecific manner. In the case of Epoxidation of conjugated cis-olefins and terminal olefins
acyclic cis-olefins, cis-epoxides were exclusively obtained with no with ketones 277 proceeds mainly via spiro transition state C,
Table 8. Epoxidation of Representative Olefins with Ketone

Catalysts 268−274
a
Isolated yield.
Figure 75. Epoxidation of various olefins with ketones 277.
Scheme 45. Synthesis of Lactone 279 via Epoxidation and

Intramolecular Cyclization
Figure 73. Asymmetric epoxidation of olefins with ketone 275.
Scheme 46. Synthesis of 2-Aryl Cyclopentanones via

Epoxidation and Rearrangement
Figure 74. Epoxidation of olefins with ketone 276. 76).182a,b,183a,184−188,190,173 van der Waals forces and/or
hydrophobic interactions could also have significant influences
on the enantioselectivity of the epoxidation.184b,185−187 In some
with the Rπ substituent of the olefin being in proximity to the cases such as nonconjugated cis-dec-4-enoic acid (Scheme 45),
oxazolidinone of the ketone catalyst due to the attractive the hydrophobic interaction plays a crucial role in stereo-
interactions between the two groups (Figure differentiation.187
Figure 76. Proposed transition states for epoxidation with ketones

277. Figure 78. Selected examples of carbohydrate-derived aldehydes and
ketones.
In subsequent studies, morpholinone-containing ketone
283a was found to be a promising catalyst for epoxidation of Table 9. Epoxidation of Representative Olefins with Ketone
challenging 1,1-disubstituted terminal olefins, giving up to 88% and Aldehyde Catalysts 284−298
ee for α-substituted styrenes (Figure 77).192a Epoxidation with
Figure 77. Epoxidation of olefins with ketone catalysts 283.
283a for this class of olefins likely proceeds mainly via planar
transition state E as a result of the attractive interaction
between the phenyl group of the substrate and the
morpholinone of the catalyst (Figure 77). Ketone 283a also
gave good ee’s for certain cis-olefins and trisubstituted olefins
(Figure 77). Ketone 283b, bearing two methyl groups on the
morpholinone moiety, was designed to incorporate the steric
features of ketone 268 (Figure 70) and the electronic
properties of 283a into one ketone with the aim to develop a epoxidation of trans-stilbene with D-glucose-derived ketone
catalyst with a broad substrate scope. Ketone 283b indeed gave 288 (10 mol %) (Table 9, entry 5).193 Epoxidation with a
generally much higher ee’s for trans-olefins and trisubstituted number of arabinose-derived ketones such as 289−291 was
olefins but lower ee’s for 1,1-disubstituted terminal olefins and subsequently reported by Shing and co-workers.194 The
cis-olefins as compared to 283a (Figure 77).192b enantioselectivity for the epoxidation increased with the size
To search for new ketone catalysts and understand their of the R group in ketone 290 (Table 9, entries 7−9),194b,c with
structural effect on catalytic properties, ketones derived from up to 90% ee being obtained for phenylstilbene using 10 mol %
various carbohydrates such as 284−287 (Figure 78, Table 9, 290c (Table 9, entry 9).194b,c However, the opposite trend was
entries 1−4) have also been investigated for epoxidation by Shi observed for epoxidation of cis-ethyl cinnamate. The epoxide
and co-workers.177 Studies showed that effective ketone was obtained in up to 68% ee with ketone 290a and could be
catalysts required a delicate balance among various factors converted into a protected side chain of Taxol (Scheme
such as steric and electronic effects. In 2002, Shing and co- 47).194d In 2003, Zhao and co-workers reported that up to 94%
workers reported that up to 71% ee was obtained for ee was obtained for epoxidation of trans-stilbene with ketone
Scheme 47. Synthesis of Protected Side Chain of Taxol Scheme 49. Synthesis of Epothilone Analogues 304 and 305
and aldehydes 292−294 (Table 9, entries 11−13).195 In 2009, diastereoselectivity (>99% de) and elaborated to pladienolides
Davis and co-workers reported a series of N-acyl-D-glucos- B and D, respectively (Scheme 50).201 In their synthesis of
amine-derived ketones such as 295 for the epoxidation (Table
9, entries 14 and 15),196 providing up to 81% ee for styrene Scheme 50. Synthesis of Pladienolides B (308) and D (311)
with ketone 295b. In their studies, Jäger and co-workers
showed that up to 80% ee could be obtained for ethyl
cinnamate with N-acetyl-D-glucosamine-derived ketone 296 (25
mol %).197 In 2009, Vega-Pérez, Iglesias-Guerra, and co-
workers described the epoxidation with glucose-derived seven-
membered-ring ketone 297. Up to 74% ee was achieved for
phenylstilbene and 1-phenylcyclohexene (Table 9, entry
17).198a,b The authors also showed that phenylstilbene was
epoxidized in 74% yield and 90% ee with mannose-derived
ketone 298 (Table 9, entry 18).198c
2.5.2. Synthetic Applications. Fructose-derived ketone
268 (Figure 70) and its enantiomer are readily accessible and
have proven to be highly effective asymmetric epoxidation pladienolide B (308), Ghosh and co-workers also utilized the
catalysts for a wide variety of trans-olefins and trisubstituted epoxidation with ketone 268 to prepare key intermediate 307
olefins. They have been widely used in the synthesis of various from olefin 306 (Scheme 50).202 In Chandrasekhar’s synthesis
complex molecules and biologically active compounds. The of pladienolide B, key intermediate 313 was obtained in 64%
synthetic applications are highlighted in this section. yield and 95% de via epoxidation of olefin 312 with ketone 268
2.5.2.1. Synthesis of Epoxide-Containing Molecules. and oxone (Scheme 51).203
Ketone 268 has been used for selective installation of the
epoxides contained in biologically and medicinally important Scheme 51. Synthesis of Pladienolide B (308)
molecules. In their synthesis of potent tumor inhibitor
cryptophycin 52 (302), Moher and co-workers examined
various epoxidation methods and employed ketone 268 and
oxone to epoxidize compound 299. The resulting epoxide was
converted to target molecule 302 in two steps (Scheme 48).199
Scheme 48. Synthesis of Cryptophycin 52 (302)
In their synthetic studies toward lituarines A−C, Smith and

co-workers showed that triene 314 could be selectively
epoxidized at the disubstituted alkene with ketone 268 and
oxone, giving epoxide 315 in 57% yield and high
diastereoselectivity (>10:1). The resulting epoxide was carried
In their synthesis of highly potent anticancer agent forward in the synthesis of the C1−C19 segments of lituarines
epothilone and its analogues,200 Altmann and co-workers A−C (Scheme 52).204
showed that epoxides 304200b and 305200c could be stereo- Site-selective epoxidation was also illustrated by Ready and
selectively obtained from macrocyclic olefin 303 in good yields co-workers in their synthesis of (+)-nigellamine A2 (319).
with ketone ent-268 and oxone (Scheme 49). Functional Epoxidation of triene 317 using ketone 268 selectively occurred
groups such as benzimidazole appear to be tolerated under the at the desired alkene with the requisite stereochemistry
epoxidation conditions. It seems that the macrocyclic ketone (Scheme 53).205
did not interfere with the epoxidation. 2.5.2.2. Intermolecular Epoxide Ring Opening. Epoxides
Pladienolides B (308) and D (311) are potent antitumor are also versatile synthetic intermediates and can be regio- and
agents. Epoxidation with ketone 268 was employed in the total stereoselectively opened by many kinds of nucleophiles to
synthesis of these two molecules by Kotake and co-workers. produce a variety of functionalized molecules. Epoxidation with
Epoxides 307 and 310 were obtained in good yield and high ketone 268 has been utilized in various synthetic processes. For
Scheme 52. Synthesis of the Segment (316) of Lituarines A− Myers and co-workers reported that differentiated trans-1,2-
C diol derivatives such as 330 and 331 were readily prepared from
silyl enol ethers in good yields and high ee’s by asymmetric
epoxidation with ketone 268 and stereospecific ring opening of
the resulting epoxides with BH3−THF and AlMe3 via an
internal delivery of the nucleophile (Scheme 56).208 As
Scheme 56. Synthesis of trans-1,2-Diol Derivatives 330 and

331
Scheme 53. Synthesis of (+)-Nigellamine A2 (319)
illustrated by Ready and co-workers in the total synthesis of

(−)-kibdelone C (335), tetraol 334 was obtained from diene
332 in 68% overall yield with >95:5 dr and >90% ee via bis-
epoxidation using ketone 268 and subsequent reduction with
borane (Scheme 57).209
example, Ollivier and co-workers reported that asymmetric
epoxidation of olefin 320 was relatively challenging but
accomplished with ketone 268 to give epoxide 321 in 43% Scheme 57. Synthesis of (−)-Kibdelone C (335)
yield and 91% ee. The resulting epoxide was converted to
heliannuol L (323) in three steps (Scheme 54).206
Scheme 54. Synthesis of Heliannuol L (323)
Davies and co-workers showed that optically active epoxide

337 could be converted to syn-fluorohydrin 338 with BF3·OEt2
in 81% yield and >99:1 diastereoselectivity via stereoselective
SN1-type epoxide ring opening. The resulting fluorohydrin was
further transformed to chiral β-fluoroamphetamine (340)
(Scheme 58).210
Scheme 58. Synthesis of β-Fluoroamphetamine (340)
In the synthesis of (−)-mesembrine (327), Taber and co-

workers showed that olefin 324 could be converted to alcohol
326 in 73% overall yield and 96% ee via epoxidation with
ketone 268, followed by epoxide ring opening with
allylmagnesium chloride (Scheme 55).207
In the synthesis of (−)-monanchorin (344), Snider and co-
Scheme 55. Synthesis of (−)-Mesembrine (327) workers reported that olefin 341 was acetalized and
subsequently epoxidized with ketone 268 in 84% yield and
90% ee. The resulting epoxide 342 was converted to
(−)-monanchorin (344) via guanidine 343 (Scheme 59).211
(+)-Monanchorin (ent-344) could be obtained in an analogous
manner via asymmetric epoxidation with ketone ent-268 as
catalyst.211 In their synthesis of zincophorin methyl ester (347),
Leighton and co-workers showed that olefin 345 could be
epoxidized with ketone 268 in 87% yield and 90% ee. Chiral
Scheme 59. Synthesis of (−)-Monanchorin (344) Scheme 62. Synthetic Studies toward Stolonidiol (356)
epoxide 346 was subsequently elaborated to target molecule

347 (Scheme 60).212 In their synthetic studies toward lyconadin A (361), Castle
and co-workers employed ketone 268 for epoxidation of olefin
Scheme 60. Synthesis of Zincophorin Methyl Ester (347) 357 to give epoxide 358 in 88% yield and >95:5 dr (Scheme
63).215 Interestingly, treatment of epoxide 358 with vinyl-
Scheme 63. Synthetic Studies toward Lyconadin A (361)
In the synthesis of (+)-lysergic acid (351) by Fujii, Ohno,

and co-workers, epoxide 349 was used as a key intermediate.
However, epoxidation of olefin 348 was found to be nontrivial. magnesium bromide and CuBr−SMe2 led to an unexpected
When mCPBA was used, the substrate decomposed under the Payne rearrangement product 359 in 81% yield, and desired
reaction conditions, giving no desired epoxide. cis-Olefins are homoallylic alcohol 360 was not obtained.
generally much less enantioselective than trans-olefins and Synthesis of (+)-(S)-ambrisentan (365) (a drug for treat-
trisubstituted olefins for epoxidation with ketone 268. Never- ment of pulmonary arterial hypertension) via asymmetric
theless, epoxide 349 was obtained in 77% yield and 82:18 epoxidation of ethyl 3,3-diphenyl acrylate with ketone 276 was
diastereoselectivity via epoxidation with 268 (Scheme 61).213 reported by Shi and co-workers (Scheme 64).216 The
Scheme 61. Synthesis of (+)-Lysergic Acid (351) Scheme 64. Synthesis of (+)-(S)-Ambrisentan (365)
compound was obtained in four steps with 53% overall yield

and >99% ee on 120 g scale. The optical purity was readily
enhanced by simple filtration to remove the much less soluble
racemic form.
Somfai and co-workers reported a divergent synthesis of four
sphingosine isomers using optically active vinyl epoxide 367 as
a common key intermediate (Scheme 65).217 Vinyl epoxide
367, obtained from epoxidation of diene 366 with ketone 268,
The resulting epoxide was transformed into propargyl alcohol was regio- and stereoselectively converted to amino alcohols
350 via silyl protection and subsequent Zn(II)-mediated 368, 370, 371, and 374. McDonald and co-workers showed
epoxide ring opening. Alcohol 350 could be further elaborated that 2-amino-3,5-diols 377 and 380 could be readily
to (+)-lysergic acid (351). synthesized via asymmetric epoxidation of olefin 375,
In the synthetic studies toward stolonidiol (356), Siegel and regioselective intermolecular or intramolecular epoxide ring
co-workers showed that trisubstituted olefin 352 was opening, and subsequent stereoselective installation of the
epoxidized with ketone 268 to give epoxide 353 in 86% yield amino groups (Scheme 66).218−220
and 9:1 diastereoselectivity. Epoxide 353 was cyclized to While relatively electron-deficient conjugated diene esters are
vinylsilane 354 in 84% yield with dilithium bis[dimethyl- less reactive, epoxidation with ketone 268 usually occurs at the
(phenyl)silyl]-cyanocuprate (Scheme 62).214 distal double bonds in high regio- and stereoselectivity.168 The
Scheme 65. Divergent Synthesis of D-erythro-Sphingosine Scheme 70. Synthesis of N-Bz-D-Ristosamine (395)
and Its Isomers
Scheme 71. Synthesis of (+)-Irciniastatin A (399)
Scheme 66. Synthesis of 2-Amino-3,5-diols 377 and 380
Scheme 72. Synthesis of the Substructure of Amphidinolide

C (404)
resulting vinyl epoxides have proven to be valuable synthetic

intermediates as illustrated in Campagne’s synthetic studies
toward octalactin A (385) (Scheme 67),221 O’Doherty’s
Scheme 67. Synthesis of Subunit of Octalactin A (385)
As shown by Kishi and co-workers in the total synthesis of

(+)-glisoprenin A (408), three of four chiral tertiary alcohols in
compound 407 were installed via tris-epoxidation of triene 405
with ketone 268 and subsequent epoxide ring opening with
LiAlH4 (Scheme 73).227
Scheme 73. Synthesis of (+)-Glisoprenin A (408)
Scheme 68. Synthesis of syn-3,5-Dihydroxy Ester 389
synthesis of protected 1,3-diol 389 (Scheme 68),222 Kitahara’s

synthesis of insecticidal tetrahydroisocoumarin 393 (Scheme
69),223 Matsushima’s synthesis of N-Bz-D-ristosamine (395)
Scheme 69. Synthesis of Tetrahydroisocoumarin 393
2.5.2.3. Intramolecular Epoxide Ring Opening. Epoxides

(Scheme 70),224 and Smith’s synthesis of (+)-irciniastatin A can undergo regio- and stereoselective intramolecular ring
(399) (Scheme 71).225 As reported by Pagenkopf and co- opening. Asymmetric epoxidation with ketone 268 has been
workers in their synthetic studies toward amphidinolide C employed to construct various optically active cyclic molecules.
(404), nonconjugated diene 400 could also be preferentially For example, Liu and co-workers reported that alkynyl
epoxidized at the trisubstituted double bond with ketone ent- epoxides, obtained from the asymmetric epoxidation using
268 (Scheme 72).226 ketone 268, could undergo tungsten-mediated [3 + 3]228a and
[3 + 2]228b cycloadditions to form optically active bicyclic Asymmetric epoxidation with ketone 268 and its enantiomer
pyrans and lactones such as 413 and 417 (Schemes 74 and 75). was applied to the synthesis of subunits of pectenotoxins (a
family of macrolides possessing potent anticancer activities)
Scheme 74. Tungsten-Mediated [3 + 3] Cycloaddition of (Figure 79) by Brimble (Scheme 78),232,233 Williams (Scheme
Alkynyl Epoxide 79),234 and Micalizio (Scheme 80).235
Figure 79. Structure of members of pectenotoxin family.
Scheme 78. Synthesis of the ABC-Ring Fragment (431) of

Scheme 75. Tungsten-Mediated [3 + 2] Cycloaddition of Pectenotoxins
Alkynyl Epoxide
In their synthesis of (+)-murisolin stereoisomer libraries,

Curran and co-workers employed the epoxidation with ketone Scheme 79. Synthesis of C1−C19 Fragment (436) of
ent-268 to stereoselectively install the epoxide onto the double Pectenotoxin 4
bond of compound 418. Tetrahydrofuran 420 was synthesized
from epoxide 419 via acid-promoted epoxide opening,
Mitsunobu inversion, and subsequent hydrolysis (Scheme
76).229a
Scheme 76. Synthesis of (+)-Murisolin and Its

Diastereoisomers
In the synthesis of (+)-sorangicin A (426) (a potent

antibiotic), Smith and co-workers showed that enyne 422
could be epoxidized with ketone 268 in high diastereoselec-
tivity. The resulting epoxide was converted to the Scheme 80. Synthesis of CDE-Ring Fragment (440) of
dioxabicyclo[3.2.1]octane fragment (425) of (+)-sorangicin A Pectenotoxin 2
(Scheme 77).230,231
Scheme 77. Synthesis of (+)-Sorangicin A

In the synthesis of 2-methyltetrahydropyran 443, a key Scheme 84. Synthesis of the Bis-Tetrahydrofuran C17−C32
intermediate toward ladder-shaped polyethers, Torikai and co- Fragment of Ionomycin
workers showed that allylic alcohol 441 could be effectively
epoxidized with ketone 268 in high stereoselectivity (>12:1 dr).
Compound 443 was readily prepared from 441 in 44% overall
yield (Scheme 81).236
Scheme 81. Synthesis of 2-Methyltetrahydropyran 443
tetrahydrofuran 459 (Scheme 85) 240 and the lactone

diastereomer (463) of the cembranolide uprolide D (464)
Floreancig and co-workers reported that tricyclic compound
(Scheme 86).241
446 could be obtained in good overall yield via sequential
epoxidation of 444 with ketone 268, formation of the
carbonate, and electron-transfer-initiated cascade cyclization Scheme 85. Synthesis of Bis-THF via Zn-initiated Epoxide
(Scheme 82).237 Cascade Cyclization
Scheme 82. Synthesis of 446 via Electron-Transfer-Initiated

Cascade Cyclization
Scheme 86. Synthesis of the Lactone Diastereomer of the

Cembranolide Uprolide D
In the total synthesis and determination of stereochemistry

of (+)-intricatetraol (450), Morimoto and co-workers reported
that olefin 447 could be epoxidized with ketone ent-268 in 87%
yield and >6:1 dr. The epoxide-opening cyclization of
compound 448 gave tetrahydrofuran 449, which was
subsequently transformed to (+)-intricatetraol (450) (Scheme
83).238
Scheme 83. Synthesis of (+)-Intricatetraol (450)
Lee, Gagné, and co-workers reported a Au(I)-catalyzed

cyclization of allenyl epoxides. For example, bis-tetrahydrofuran
468 was obtained with 55% yield and 11:1 dr when allenyl
epoxide 467 was treated with (PhO)3PAuCl catalyst (Scheme
87).242
In the synthesis of bis-tetrahydrofuran C17−C32 segment In the synthesis of Lycopodium alkaloid (−)-8-deoxyserrati-
(455) of antibiotic ionomycin (456), Marshall and co-workers nine (471), Yang and co-workers showed that the desired
utilized ketone 268 to epoxidize olefin 451 to give compound epoxide was obtained as the sole product in 60% yield via
452, which was converted to bromide 453. Treating 453 with epoxidation of olefin 469 with ketone 268 (Scheme 88).243
Zn and TBAI led to formation of vinyl bis-tetrahydrofuran 454 However, the undesired diastereomer was predominantly
via Zn-initiated reduction−elimination and in-situ cyclization. formed when mCPBA was used.
Compound 454 was further elaborated to bis-tetrahydrofuran Prenylphenol derivatives have been shown to be effective
C17−C32 segment 455 (Scheme 84).239 Marshall and co- substrates for epoxidation with ketone 268 or 276. Higher ee’s
workers also employed this asymmetric epoxidation/Zn- were obtained with ketone 276 than 268 in some cases. The
initiated epoxide cascade cyclization to synthesize bis- resulting chiral epoxides were elaborated to various biologically
Scheme 87. Au(I)-Catalyzed Cyclization of Allenyl Epoxide (489) (Scheme 92),247 and Woggon’s synthesis of α-
tocopherol (494) (Scheme 93).248
Scheme 92. Synthesis of (+)-Marmesin, (−)-(3′R)-

Decursinol, and (+)-Lomatin
Scheme 88. Synthesis of (−)-8-Deoxyserratinine (471)
Scheme 93. Synthesis of α-Tocopherol (494)
active dihydrobenzofurans and dihydrobenzopyrans as illus-

trated in Coster’s synthesis of (+)-angelmarin (474) (Scheme
89)244 and methyl (+)-7-methoxyanodendroate (477) (Scheme
Scheme 89. Synthesis of (+)-Angelmarin (474)
Kan and co-workers employed the ketone 276-catalyzed

epoxidation in the synthesis of (−)-5,7-dideoxy-gallocatechin
gallate (498). Epoxidation of olefin 495 with ketone 276 and
subsequent intramolecular acid-promoted cyclization provided
dihydrobenzopyran 497, which was further transformed to
target compound 498 (Scheme 94).249
Scheme 94. Synthesis of (−)-5,7-Dideoxy-Gallocatechin

Gallate (498)
Scheme 90. Synthesis of Methyl (+)-7-

Methoxyanodendroate (477)
90),245 Kimachi’s synthesis of rhinacanthin A (481)246a and

(−)-dehydroiso-β-lapachone (483)246b (Scheme 91), Hamada’s
synthesis of (+)-angelmarin (474) (Scheme 89),247 (+)-mar-
mesin (486), (−)-(3′R)-decursinol (487), and (+)-lomatin
Scheme 91. Synthesis of Rhinacanthin A (481) and Synthesis of chiral hydroxy lactones via asymmetric
(−)-Dehydroiso-β-lapachone (483) epoxidation of alkenyl carboxylic acids has been reported. In
their synthesis of hydroxy lactone 503, a key pharmaceutical
intermediate, a team at DSM Pharma Chemicals showed that
the asymmetric epoxidation process could be carried out on an
industrial level. Hydroboration of 4-pentynoic acid lithium salt
and subsequent Suzuki coupling with 3-fluorobenzyl chloride
gave alkene 501. Epoxidation of 501 with ketone 268 and in-
situ lactonization yielded 59 lb of lactone 503 in 63% overall
yield and 88% ee (Scheme 95).250 Sudalai and co-workers
reported that lactone 507 was obtained in 62% yield and 92%
ee via epoxidation of alkene 506 with ketone 268 and in-situ
lactonization. Lactone 507 was elaborated to (+)-L-733,060
(508), a NK1 receptor antagonist (Scheme 96).251,252 Sewald
Scheme 95. Pilot-Plant-Scale Synthesis of Lactone 503 Scheme 99. Synthesis of Renin Inhibitor DS-8108b
Scheme 96. Synthesis of NK1 Receptor Antagonist (+)-L-

733,060 (508)
Cs-symmetric penta-THF 523 (Scheme 100).256 Morimoto and

co-workers reported that monotetrahydrofuran 522 was
Scheme 100. Synthesis of Initially Assigned Glabrescol (523)
and co-workers utilized the epoxidation to form lactone 510,

which was converted to cryptophycin-39 unit A precursor
(512) (Scheme 97).253 Asymmetric epoxidation with ketone
Scheme 97. Synthesis of Cryptophycin-39 Unit A Precursor obtained from diene 521 in 69% overall yield and 15:1 dr via
(512) epoxidation and subsequent CSA-promoted cyclization and
elaborated to antiplasmodial C2-symmetric (+)-ekeberin D4
(525) (Scheme 101).257
Scheme 101. Synthesis of (+)-Ekeberin D4 (525)
268 and in-situ lactonization process was also effectively

employed by Nakamura and co-workers in their synthesis of In their synthetic studies toward thyrsiferol (531)258 and
renin inhibitors 516 (Scheme 98)254 and DS-8108b (520) thyrsenol A (532)259 (Scheme 102), McDonald and co-workers
(Scheme 99).255 showed that the internal double bond of compound 526 was
site and stereoselectively epoxidized with ketone 268 to give
epoxide 527. Under carefully controlled reaction conditions,
Scheme 98. Synthesis of Renin Inhibitor 516
one of the bromohydrin epoxide diastereomers preferentially
cyclized to give bromotetrahydropyran 528 in 50% yield.
Scheme 102. Synthesis of Substructure 529 and

Dideoxydidehydrothyrsenol (530)
When two or more alkenes are present in a molecule, steric

and electronic differences around the double bonds allow the
epoxidation to proceed site selectively as illustrated in various
cases. For example, in the synthesis of initially assigned
glabrescol (523) reported by Kodama and co-workers, diene
521 was regio- and stereoselectively epoxidized using ketone
268 to afford monotetrahydrofuran 522 in 89% yield and 10:1
dr after the concomitant ring closure. Further elaboration gave
In the total synthesis of bromotriterpene polyether Njardarson and co-workers reported that epoxidation of
(+)-aurilol (539) reported by Morimoto and co-workers, triene 548 with ketone 268 occurred selectively at the
compounds 533 and 536 were epoxidized with ketone 268 and trisubstituted alkene, giving vinyl epoxide 549 in 72% yield
its enantiomer to give epoxides 534 and 537 in high and >20:1 dr. The epoxide was subsequently elaborated to
diastereoselectivities (Scheme 103).260 Epoxidation of 536 several heterocycle-containing labdane natural products such as
occurred site selectively at the trisubstituted alkene. 551 and 552 (Scheme 106).263
Scheme 103. Synthesis of (+)-Aurilol (539) Scheme 106. Synthesis of Labdane Natural Products 551 and
552
McDonald and co-workers reported that triene 553 was site-

and stereoselectively epoxidized with ketone 268, giving bis-
epoxide 554 in 76% yield and >20:1 dr. The bis-epoxide was
In their synthetic studies toward terpendole E (543), Oikawa further transformed to ent-nakorone (ent-557) and ent-abudinol
and co-workers reported that asymmetric epoxidation of diene B (ent-558) in a biomimetic fashion (Scheme 107).264 In
540 with ketone 268 occurred selectively at the trisubstituted
double bond, giving epoxide 541 in 90% yield and 4:1 dr. Upon Scheme 107. Biomimetic Synthesis of ent-Nakorone and ent-
cyclization and deprotection, epoxide 541 was converted to the Abudinol B
DEF-ring terpenoid fragment of terpendole E (Scheme 104).261
Scheme 104. Synthesis of the DEF-Ring Terpenoid

Fragment (542) of Terpendole E
another synthetic route to ent-abudinol B (ent-558), McDonald

and co-workers showed that the two trisubstituted alkenes in
563 were selectively epoxidized with ketone 268. The
Huo and co-workers reported the synthesis of (+)-ner-
unreacted terminal alkene subsequently participated in
oplofurol (547) via asymmetric dihydroxylation of (+)-ner-
TMSOTf-promoted cyclization to form ent-abudinol B (ent-
olidol (544), site- and stereoselective epoxidation of the
558) in 15% yield (Scheme 108).265
trisubstituted alkene of compound 545 with ketone 268, and
Wiemer and co-workers reported that monoepoxides 566
subsequent in-situ cyclization (60% overall yield) (Scheme
could be obtained with high ee’s via site- and stereoselective
105).262
epoxidation of the terminal trisubstituted alkene of dienes 565.
Acid-promoted cyclization of epoxides 566 led to hexahydrox-
Scheme 105. Synthesis of (+)-Neroplofurol (547) anthenes 567, which were subsequently elaborated to
schweinfurthins G (568),266 B (569), and E (570)267 as well
as related compound (+)-vedelianin (571)268 and schweinfur-
thin analogue 572269 (Scheme 109).
Siegel and co-workers reported that epoxidation of
commercially available (−)-caryophyllene (573) with ketone
ent-268 site selectively occurred at the trisubstituted alkene,
giving diastereomeric epoxides 575 and 574 in a ratio of 2.2:1,
while these two epoxides were formed in a ratio of 1:5 favoring
Scheme 108. Biomimetic Synthesis of ent-Abudinol B (ent- Scheme 111. Synthesis of (−)-Seragakinone A (581)
558)
Scheme 112. Synthesis of Sponge Meroterpenoid Pelorol

Analogue (586)
Scheme 109. Synthesis of Schweinfurthins and Vedelianin
The more reactive alkene a was selectively epoxidized with

ketone ent-268, followed by addition of ketone 276 to complete
the epoxidation of the less reactive alkene b (Scheme 113).273
Scheme 113. Synthesis of Lactodehydrothyrsiferol (590)
574 when mCPBA was used. Treating epoxide 575 with

diphenyl phosphate and magnolol (576) led to a single-step
formation of caryolanemagnolol (577) in 15% yield (Scheme
110).270
Scheme 110. Synthesis of Caryolanemagnolol (577)
When a substrate contains multiple alkenes, all double bonds

can be simultaneously epoxidized with ketone 268 or its
enantiomer, allowing the rapid increase of molecular complex-
ity via epoxide-ring-opening cyclization.274 For example, in the
synthesis of (−)-longilene peroxide (593) reported by
Morimoto and co-workers, two tetrahydrofuran rings were
made via asymmetric bis-epoxidation of diene 591 with ketone
ent-268 and subsequent TFA-promoted epoxide-opening
cyclization (Scheme 114).275 Morimoto and co-workers also
employed the bis-epoxidation to synthesize (+)-enshuol (597)
and determine its absolute configuration. Diene 594 was
Suzuki and co-workers reported that the trisubstituted alkene epoxidized with ketone 268 to give diepoxide 595 in 74% yield
of 578 was site- and stereoselectively epoxidized with ketone and >6:1 dr. Acid-promoted epoxide-opening cascade cycliza-
ent-276, giving epoxide 579 in 92% yield and 8.2:1 dr. Epoxide- tion of 595 yielded compound 596, which was elaborated to
opening cyclization of 579 and further elaboration led to (+)-enshuol (597) (Scheme 115).276
(−)-seragakinone A (581) (Scheme 111).271 In their studies on electron-transfer-initiated cascade
Sponge meroterpenoid pelorol analogues such as 586 were cyclizations, Floreancig and co-workers utilized ketone catalyst
synthesized by Andersen and co-workers. The epoxide in 583 268 for epoxidation of diene 598, giving bis-epoxide 599 in
was installed via site- and enantioselective epoxidation of diene 85% yield. Bis-epoxide 599 was converted to bis-tetrahydrofur-
582 with ketone ent-268. InBr3-promoted cyclization of an 600 in 66% yield upon photoirradiation (Scheme 116).277
epoxide 584 led to construction of polycyclic structure 585, Synthesis of (−)-heronapyrrole C (604) via a cascade
which was converted to compound 586 (Scheme 112).272 cyclization was reported by Stark and co-workers. Bis-epoxide
In the synthesis of lactodehydrothyrsiferol (590), Floreancig 602 was generated by asymmetric epoxidation of diene 601
and co-workers showed that bis-epoxide 588 could be obtained using ketone ent-268 and converted to bis-tetrahydrofuran 603
in 82% yield via one-pot sequential epoxidations of diene 587. in 60% overall yield (Scheme 117).278
Scheme 114. Synthesis of (−)-Longilene Peroxide (593) Scheme 118. Synthesis of Tetrahydrofuran Lactones 607 and
609
Scheme 119. Synthesis of Teurilene (612) by Martiń
Scheme 115. Synthesis of (+)-Enshuol (597)
Scheme 116. Synthesis of Bis-THF via Electron-Transfer- with ketone ent-268 and subsequently transformed to
Initiated Cascade Cyclizations tetraepoxide 615. Treating 615 with TfOH led to direct
formation of teurilene (612) via an epoxide-opening cascade
triggered by hydrolysis of the terminal epoxide (Scheme
120).281
Scheme 120. Synthesis of Teurilene (612) by Morimoto
Scheme 117. Synthesis of (−)-Heronapyrrole C (604)
Sinha and co-workers employed the epoxidation with ketone

268 and ent-268 in the synthesis of a library of bis-THF
annonaceous acetogenins. For example, bis-THF lactone 607 Corey and co-workers reported that polyene 616 was
was obtained from 605 via bis-epoxidation and subsequent stereoselectively and simultaneously epoxidized with ketone
CSA-mediated cyclization in 72% overall yield. Interestingly, 268 to give pentaepoxide 617, which was converted to initially
alkene a in substrate 605 could be selectively epoxidized by assigned Cs-symmetric glabrescol (523) in 31% overall yield
controlling the reaction conditions, giving mono-THF lactone (Scheme 121).282 In their studies on the determination of the
609 in 54% overall yield upon cyclization with CSA (Scheme correct structure of glabrescol, C2-symmetric pentacyclic
118).279 oxasqualenoid 621, prepared via tetraepoxidation of polyene
Martiń and co-workers synthesized teurilene (612) via 618 and subsequent cyclization, matched the reported isolated
epoxide-opening cascades (Scheme 119).280 Epoxidation of natural product glabrescol (Scheme 122).283,284
olefin 610 with ketone 268 gave epoxide 611 (81% yield), Qu and co-workers reported that glabrescol (621) was
which could be elaborated to teurilene (612). Morimoto and synthesized in two steps from polyene 622 or squalene (624)
co-workers reported a biomimetic synthesis of teurilene. via polyepoxidation with ketone ent-268 and base-promoted
Epoxide 614 was prepared via asymmetric epoxidation of 613 middle-to-terminal double epoxide-opening cascade cyclization
Scheme 121. Synthesis of Initially Assigned Glabrescol (523) Scheme 123. Synthesis of (−)-Glabrescol (621) by Qu
Scheme 122. Synthesis of Revised (−)-Glabrescol (621) by

Corey
Scheme 124. Synthesis of (±)-Glabrescol (621) by

Morimoto
(Scheme 123).285 The results suggested two alternative

biogenetic approaches to (−)-glabrescol.
Morimoto and co-workers showed that meso-hexaepoxide
628, prepared via site- and stereoselective epoxidation of
compound 626 with ketone ent-268 and subsequent reduction,
underwent an acid-promoted biomimetic epoxide-opening
cascade cyclization to give (±)-glabrescol (621) in 8% yield
(Scheme 124).281
In the initial synthesis of (+)-omaezakianol (another member
of the oxasqualenoid family) reported by Morimoto and co-
workers, diepoxide 630 and triepoxide 634 were prepared via
epoxidation with ketone ent-268 and ketone 268, respectively.
Monotetrahydrofuran 632, derived from 630, was coupled with
634 via cross metathesis to give triepoxide 635, which was opening cascade cyclization, and reduction with Na (Scheme
elaborated to (+)-omaezakianol (637) (Scheme 125).286 In 127).287
their second-generation synthesis of (+)-omaezakianol, Mor- In studies on the biosynthesis of lasalocid A (647) by Oguri,
imoto and co-workers showed that pentaepoxide 640, prepared Oikawa, and co-workers, bis-epoxide 646, a proposed substrate
via epoxidation of polyene 638 with ketone ent-268 and for epoxide hydrolase Lsd19, was prepared via epoxidation of
subsequent transformations, was directly converted to diene 644 with ketone 268 and subsequent deprotection.
(+)-omaezakianol (637) in 33% yield via aforementioned Lasalocid A (647) was indeed formed via 5-exo-6-endo
acid-promoted biomimetic epoxide-opening cascade cyclization cyclization when 646 was incubated with Lsd19. On the
(Scheme 126).281 other hand, 5-exo-5-exo cyclization product 648 was obtained
Xiong, Corey, and co-workers reported a three-step synthesis when 646 was treated with trichloroacetic acid (Scheme
of (+)-omaezakianol (637) from racemic chlorohydrin 641 via 128).288 These studies provide useful insights into polyether
pentaepoxidation with ketone 268, CSA-promoted epoxide- biosynthesis.
Scheme 125. Synthesis of (+)-Omaezakianol (637) by Scheme 128. Biosynthesis of Lasalocid A (647)
Morimoto
Scheme 126. Synthesis of (+)-Omaezakianol (637) by

Morimoto Scheme 129. Proposed Biosynthetic Pathway for Brevetoxin
B (651)
Scheme 127. Synthesis of (+)-Omaezakianol (637) by Xiong

and Corey
polyene−polyepoxide−polycyclization process could rapidly

construct stereochemically complex molecules from simple
polyene precursors and would present a synthetically attractive
and powerful strategy for synthesis of polyethers. Epoxidation
with ketone 268 has proven to be a valuable method for such
studies.
Murai and co-workers reported that triepoxide 653 was
obtained in 56% yield via tris-epoxidation of 652 with ketone
268. Tricyclic ether 654 was formed in 9.3% yield from the
triepoxide via La(OTf)3-catalyzed cascade cyclization upon
desilylation (Scheme 130).291
Scheme 130. Synthesis of Fused Tricyclic Ether 654
Fused polycyclic ethers such as brevetoxin B (651) are a class

of biologically important molecules and may biosynthetically
derive from polyenes via polyepoxidation and epoxide-opening
cascade endo cyclization (Scheme 129).289,290 The biomimetic
McDonald and co-workers reported various studies on Scheme 134. Synthesis of HIJK-Ring Fragment (668) of
biomimetic synthesis of fused polycyclic ethers.292 For example, Gymnocin A
triene 655 was epoxidized with ketone 268 to introduce three
epoxides. Tetracyclic ether 657 was obtained in 20% overall
yield from tetraepoxide 656 via Lewis acid-promoted cascade
endo cyclization and subsequent acetylation (Scheme 131).292e
Scheme 131. Synthesis of Fused Polycyclic Ether 657 via

Polyepoxide Cyclization
transformed to target molecule 676 (Scheme 135).298 They

Jamison and co-workers reported Si-directed formation of also accomplished the total synthesis of armatol A (680) and
fused polycyclic ethers. Triepoxide 659 was obtained from
vinylsilane 658 in 50% yield and 9:1 dr via tris-epoxidation with Scheme 135. Synthesis of ent-Dioxepandehydrothyrsiferol
ketone 268. Tetracyclic tetrahydropyran 660 was formed in (676)
20% overall yield via an epoxide-opening cascade cyclization of
triepoxide 659 promoted by Cs2CO3/CsF and acetylation
(Scheme 132).293 The trimethylsilyl groups directed 6-endo
Scheme 132. Synthesis of Tetrahydropyran 660 via TMS-

Directed Cyclization
determined its absolute configuration. Three trisubstituted

alkenes of tetraene 677 were stereoselectively epoxidized using
ketone 268, with the terminal alkene being untouched.
cyclizations and “disappeared” after each cyclization.294,295 Tricyclic ether 679 was obtained in 18% overall yield via
Their subsequent studies showed that triepoxide 663, obtained BF3·OEt2-promoted cyclization of triepoxide 678, followed by
from tris-epoxidation of triene 661 with ketone 268 and acetylation, and further elaborated to armatol A (680) (Scheme
deprotection, underwent 6-endo cyclizations to form tetracyclic 136).298b
tetrahydropyran 664 without the need for directing groups
when the reaction was carried out in water (Scheme 133).296 Scheme 136. Synthesis of Armatol A (680)
This methodology was applied to the synthesis of the HIJK-ring
fragment (668) of gymnocin A (Scheme 134).297
Jamison and co-workers reported the total synthesis of ent-
dioxepandehydrothyrsiferol (676) via bromonium-initiated
cascade cyclization. Diepoxide 673 was prepared via
epoxidation of 672 with ketone 268 in 75% yield and was
further elaborated to triepoxide 674. Polycyclic compound 675
was obtained in 36% yield by treating 674 with NBS and
2.6. Chiral Iminium Salt-Catalyzed Epoxidation
Scheme 133. Synthesis of Tetrahydropyran 664 via Water-
Promoted Cyclization Like dioxiranes, oxaziridinium salts are a class of effective agents
for epoxidation of olefins, and they can be generated in situ
from the corresponding iminium salts and oxidants, typically
Oxone. Upon epoxidation of the olefin, the iminium salt is
regenerated. A catalytic asymmetric epoxidation could be
realized when a chiral iminium salt catalyst is used (Scheme
137).299
In 1976, Lusinchi and co-workers reported that an
oxaziridinium salt (683) (Figure 80) could be prepared via
methylation of the corresponding oxaziridine with FSO3Me or
Scheme 137. Chiral Iminium Salt-Catalyzed Asymmetric Table 10. Epoxidation of Representative Olefins with
Epoxidation Iminium Salt Catalysts 687−692a
Figure 80. Oxaziridinium and iminium salts.

a
by oxidation of the corresponding iminium salt with a Reactions were carried out with olefin, iminium salt (5−10 mol %),
peracid.300 Subsequently, Hanquet and co-workers reported oxone, and inorganic base (NaHCO3 or Na2CO3) in CH3CN−H2O at
0 °C unless otherwise stated. bReactions were carried out at rt.
that oxaziridinium salt 684 could be similarly prepared by c
Reactions were carried out with NaOCl in the presence of 25 mol %
methylation or oxidation method,301 and it was found to be K2CO3 in CH2Cl2. dReactions were carried out with TPPP in CHCl3
highly reactive for epoxidation of olefins.302 They further at −40 °C. eThe reaction was carried out with mCPBA in CH2Cl2.
showed that the epoxidation could be run with a catalytic
amount of the corresponding iminium salt (685) (Figure 80) was epoxidized in 78% yield and 73% ee with 10 mol %
using oxone−NaHCO 3 in CH 3 CN−H2 O or mCPBA− iminium salt 688 in the presence of oxone and Na2CO3 in
NaHCO3 in CH2Cl2.303,304 A wide variety of chiral iminium CH3CN−H2O (Table 10, entry 2).306a Rozwadowska and co-
salts, such as dihydroisoquinoline-, binaphthylazepinium-, workers reported that stilbene oxide could be obtained in 70%
biphenylazepinium-based iminium salts, have been investigated yield and 45% ee with 10 mol % (+)-thiomicamine-derived
for the epoxidation. iminium salt 692 and mCPBA (Figure 81) (Table 10, entry
2.6.1. Dihydroisoquinoline-Based Iminium Salts. An 10).308
early example employing an oxaziridinium salt for asymmetric Iminium salt 690c was found to be an effective catalyst for
epoxidation of olefins was reported by Bohé and co-workers in epoxidation of some cis-olefins, giving up to 97% ee for 2,2-
1993.305 Several unfunctionalized olefins were epoxidized with dimethyl-6-cyanochromene by running the reaction under
1.1 equiv of recrystallized oxaziridinium salt 686 (Figure 81), nonaqueous conditions (in CHCl 3 ) at −40 °C with
tetraphenylphosphonium monoperoxysulfate (TPPP) as the
oxidant (Figure 82).309,307d The resulting epoxide (693) was
Figure 82. Epoxidation of cis-olefins with iminium salt catalyst 690c.
Figure 81. Dihydroisoquinoline-based oxaziridinium and iminium converted to levcromakalim (694) (an antihypertensive agent)
salts. with pyrrolidin-2-one and NaH in 52% yield (Scheme 138).309
Total synthesis of (−)-lomatin (ent-489) and (+)-(3′S,4′R)-
giving up to 42% ee for trans-stilbene.305b Stilbene oxide was trans-khellactone (697) was also achieved using iminium salt
obtained in 79% yield and 35% ee when the epoxidation was
run with 5 mol % iminium salt 687, oxone (1.3 equiv), and Scheme 138. Synthesis of Levcromakalim (694)
NaHCO3 (4 equiv) in CH3CN−H2O (Table 10, entry 1).305b
Page and co-workers reported a number of dihydroisoquino-
line-based iminium salts, such as 688−691, with chiral moieties
attached on the iminium nitrogen (Figure 81).306,307 This type
of iminium salt catalyst was readily prepared from various chiral
primary amines, and they were extensively investigated for
epoxidation of olefins (Table 10, entries 2−9). trans-Stilbene
690c-catalyzed epoxidation as the key step (Scheme 139).310 Table 11. Epoxidation of Representative Olefins with
Epoxide 696 was obtained in 65% yield and 97% ee from Iminium Salt Catalysts 698−708a
Scheme 139. Synthesis of (−)-Lomatin and (+)-trans-

Khellactone
seselin 695 with TPPP as oxidant under nonaqueous

conditions. Reductive cleavage of the epoxide with NaBH3CN
afforded (−)-lomatin (ent-489) in 92% yield. (+)-Khellactone
(697) was obtained in 95% yield by epoxide opening with
H2SO4. Epoxidation with catalyst 690c was also applied to the
kinetic resolution of racemic 2-substituted chromenes, giving
up to 99% ee for the epoxide.311
2.6.2. Binaphthylazepinium-Based Iminium Salts. A
series of binaphthylazepinium-based chiral iminium salt
catalysts such as 698−708 have been studied for epoxidation
of olefins (Figure 83, Table 11). In 1996, Aggarwal and co- a
Reactions were carried out with olefin, iminium salt (5 mol %),
oxone, and inorganic base (NaHCO3 or Na2CO3) in CH3CN−H2O at
0 °C unless otherwise stated. bReactions were carried out with TPPP
in CH3CN at −40 °C. c2.5 mol % 18-crown-6 was added, and
CH2Cl2−H2O (3:2, v/v) was used as solvent. d2.5 mol % iminium salt
was used.
pseudoaxial substituent at a carbon atom adjacent to the

nitrogen in the binaphthylazepinium-based iminium salt could
improve enantioselectivity for epoxidation of some olefins.315
For example, 94% ee was achieved for epoxidation of 1-
phenylcyclohexene with iminium salt 702 (Table 11, entry
7).315
In 2006, Lacour and co-workers reported a number of
binaphthyl-based iminium salts with TRISPHAT as counterions
such as 703−706 (Figure 83),316 and up to 87% ee was
obtained for epoxidation of 1-phenyl-3,4-dihydronaphthalene
Figure 83. Binaphthylazepinium-based iminium salts. (Table 11, entry 11).316b The studies showed that the epoxide’s
stereochemistry was determined by the configuration of the
binaphthyl group of the iminium salt catalyst but not by the
workers reported the preparation and use of binaphthyl-based configuration of the N-substituent. In their efforts to elucidate
iminium salt catalyst 698 for asymmetric epoxidation.312 For the structural parameters needed for high asymmetric induction
example, 1-phenylcyclohexene was epoxidized with 5 mol % in epoxidation, Lacour and co-workers showed that H8-
698 in the presence of oxone and NaHCO3 in CH3CN−H2O binaphthyl-based iminium salts 707 and 708 with a larger
to give the epoxide in 80% yield and 71% ee (Table 11, entry dihedral angle around the biaryl twist gave high enantiose-
1). lectivity for the epoxidation (Table 11, entries 12−14).317 It
In 2004, Page and co-workers reported a highly enantiose- was shown that the counteranion was important for the
lective iminium salt catalyst (699) (Figure 83), achieving up to catalyst’s reactivity and selectivity, with SbF6− being optimal.317
95% ee for epoxidation of 1-phenyl-3,4-dihydronaphthalene Iminium salt 707b proved to be very effective in the
(Table 11, entry 2).313 This catalyst was shown to be very epoxidation of a variety of trisubstituted olefins, giving up to
active as demonstrated by the low catalyst loading (0.1 mol %) 98% ee (Figure 84).317b,c
and the short reaction time for epoxidation of 1-phenyl- 2.6.3. Biphenylazepinium-Based Iminium Salts. Page
cyclohexene.313a Page and co-workers also reported a range of and co-workers investigated a number of biphenylazepinium
binaphthyl-based iminium salts achiral at the nitrogen atom.314 salt catalysts such as 709−713 for epoxidation (Figure
Among them, catalysts 700a and 700b were found to be most 85).307b,c,e,313c,315,318,319 Various oxidants were examined for
enantioselective, giving 82% and 84% ee for epoxidation of 1- the reaction with iminium salt 710 (Table 12, entries 2−
phenylcyclohexene, respectively (Table 11, entries 4 and 5).314 7),307b,e,318,313c giving up to 70% ee for 1-phenylcyclohexene
Recently, Page and co-workers reported that introducing a with TPPP in CH2Cl2−CH3CN at −78 °C (Table 12, entry
cyclohexene (Table 12, entry 9).315 2,2-Dimethyl-6-cyanochro-

mene was epoxidized in 100% conversion and 98% ee with 712
(10 mol %) and TPPP (2 equiv) in CHCl3 at 0 °C.315
Epoxidation with iminium salt 710 was applied to the total
synthesis of (+)-scuteflorin A (721) (Scheme 140).320
Scheme 140. Synthesis of (+)-Scuteflorin A (721)
Figure 84. Epoxidation of trisubstituted olefins using iminium salt

707b.
Xanthyletin 717 was efficiently epoxidized with catalyst 710
and TPPP to give epoxide 718 in 97% yield and >99% ee. The
epoxide was converted to target molecule 721 via acid-
promoted epoxide ring opening, selective oxidation, and
esterification with 3,3-dimethyl acryloyl chloride.
Lacour and co-workers reported their studies on the
epoxidation with biphenylazepinium salts bearing TRISPHAT
as counterions such as 714−716 (Figure 85).321,316b,322 Up to
85% ee was obtained for 1-phenyl-3,4-dihydronaphthalene with
doubly bridged biphenylazepinium salt catalyst 716 (Table 12,
entry 13).322
Figure 85. Biphenylazepinium-based iminium salts. Lacour and co-workers reported that binaphthyl and
biphenyl azepines 722−725 (Figure 86) could be directly
Iminium Salt Catalysts 709−716a
Figure 86. Binaphthyl and biphenyl azepines 722−727.
Table 13. Epoxidation of Representative Olefins with Biaryl

Azepine Catalysts 722−727a
a
Reactions were carried out with olefin, iminium salt (5 mol %),
oxone, and inorganic base (NaHCO3 or Na2CO3) in CH3CN−H2O at
0 °C unless otherwise stated. bReactions were carried out with catalyst
(10 mol %) and TPPP in CH3CN at −40 °C. cReactions were carried
out with catalyst (10 mol %) and TPPP in CH2Cl2−CH3CN at −40 or
−78 °C. d20 mol % of catalyst and electrochemically generated
persulfate was used as the oxidant. e10 mol % of catalyst and H2O2 was
used as the oxidant. f10 mol % of catalyst and NaOCl was used as the
oxidant. g2.5 mol % 18-crown-6 was added, and CH2Cl2−H2O (3:2, v/
v) was used as solvent.
a
Reactions were carried out with olefin, catalyst (5−10 mol %), oxone,
and NaHCO3 in CH3CN−H2O at 0 °C unless otherwise stated. b2.5
4).313c Biphenyl-based iminium salt 712 with a pseudoaxial mol % 18-crown-6 was added, and CH2Cl2−H2O (3:2, v/v) was used
methyl group gave 82% ee for epoxidation of 1-phenyl- as solvent.

used as catalysts for epoxidation of olefins (Table 13, entries 1−

4).316 Up to 86% ee was obtained for 1-phenylcyclohexene
using catalyst 724 and oxone (Table 13, entry 3).316b In their
studies, Page and co-workers showed that up to 81% ee was
achieved in the epoxidation of unfunctionalized olefins with
binaphthyl azepine 726 as catalyst (Table 13, entry 5).323 It was Figure 89. Pyrrolidine-based amine and amine HCl salt catalysts.
postulated that the amine was oxidized in situ to the
corresponding iminium salt, which catalyzed the epoxidation.323
2.6.4. Exocyclic Iminium Salts. Chiral exocyclic iminium
salts have also been investigated for asymmetric epoxidation of
olefins. In 1999, Armstrong and co-workers reported that 1-
phenylcyclohexene was epoxidized in 100% conversion and
22% ee with stoichiometric iminium salt 728 and oxone (Figure
87) (Table 14, entry 1).324 Epoxidation with ketiminium salt
Figure 90. Epoxidation of olefins with amine or amine salt catalyst.
was obtained for epoxidation of 1-phenylcyclohexene with 10

Figure 87. Exocyclic iminium salts. mol % 733 (Figure 90).328 Studies indicated that the
protonated ammonium salt likely acted as a phase-transfer
Table 14. Epoxidation of Olefins Using Isolated or in-Situ- catalyst to bring the oxidant into the organic phase and as an
Generated Exocyclic Iminium Salts activator of the oxidant via hydrogen bonding (Figure
91).328,329
catalyst 729 was described by Komatsu and co-workers in

2000.325 Cinnamyl alcohol was epoxidized in 70% yield and
39% ee with 10 mol % 729 (Table 14, entry 2). In 2001, Wong,
Yang, and co-workers reported an epoxidation process Figure 91. Possible forms of pyrrolidinium peroxymonosulfate.
involving in-situ generation of iminium salts from chiral amines
and aldehydes (Figure 88).326 Up to 65% ee was obtained for In 2005, Yang and co-workers investigated a number of
trans-stilbene with amine 731 and aldehyde 732 (Table 14, pyrrolidine-based chrial amine catalysts such as 150 and 734 for
entry 4). epoxidation of unfunctionalized olefins (Figure 92).330 With
Figure 88. Iminium salt precursors.
2.7. Chiral Amine or Chiral Amine Salt-Catalyzed

Epoxidation Figure 92. Epoxidation of olefins with catalysts 150 and 734.
During their studies on iminium salt-catalyzed epoxidations of
olefins, Aggarwal and co-workers discovered that test substrate
1-phenylcyclohexene could be epoxidized by simple amines fluorinated catalyst 150 or 734, up to 61% ee was achieved for
with oxone as oxidant.327 Both secondary and tertiary amines epoxidation of 1-phenylcyclohexene using oxone buffered with
were effective promoters. Among the amines examined, NaHCO3. It was believed that the electronegative fluorine atom
pyrrolidine gave the highest conversion for 1-phenylcyclohex- may stabilize ammonium salts through hydrogen bonding and
ene. Asymmetric induction was also observed with chiral amine charge−dipole interactions (Figure 93), which was beneficial
catalyst 149 (Figure 89).327 In their subsequent studies, for the catalytic efficiency.330 Shi and co-workers showed that
Aggarwal and co-workers found that the HCl salt of amine cis-1-propenylphosphoric acid potassium salt (735) could be
149 gave more consistent and reproducible results as well as a epoxidized in 100% conversion and 74% ee using amine catalyst
higher ee value than 149 itself (Figure 90).328 Up to 66% ee 737 and H2O2−CH3CN (Scheme 141).331,332
Scheme 142. Proposed Mechanism for Epoxidation with

Aspartic Acid-Based Catalysts
Figure 93. Stabilization of the ammonium salts.
Scheme 141. Epoxidation of cis-1-Propenylphosphoric Acid

Salt with Amine 737
2.8. Aspartic Acid-Based Peptide-Catalyzed Epoxidation

Miller and co-workers reported the electrophilic epoxidation of
olefins using aspartic acid-based peptide catalysts such as 738−
740 (Figure 94). Various carbamate-containing olefins were
Figure 94. Aspartic acid-based peptide catalysts 738−740.
epoxidized with peptide 738 as catalyst and H2O2 or urea−

H2O2 (UHP) as oxidant, giving the corresponding epoxides in
73−99% yield and up to 92% ee (Figure 95).333,334 Epoxidation
Figure 96. Epoxidation of polyenes with aspartic acid-based catalysts

744 and 745.
geranylgeraniol, the 6,7-olefin was site-selectively epoxidized

with catalyst 745, affording the corresponding epoxide in 42%
yield.
3. ORGANOCATALYZED ASYMMETRIC
Figure 95. Epoxidation of olefins with aspartic acid-based catalysts AZIRIDINATION OF OLEFINS
738−740.
Asymmetric aziridination of olefins provides a useful strategy
likely proceeds via a chiral carboxylic acid/peracid cycle. The for preparation of optically active aziridines,336 which are
carboxyl group of the catalyst is first activated by important building blocks in organic synthesis and can be regio-
diisopropylcarbodiimide (DIC) to form intermediate 742, and stereoselectively transformed to various nitrogen-contain-
which reacts with H2O2 to form the transient peracid 743. ing molecules. During the past few years, significant progress
Upon epoxidation of the olefin, the carboxylic acid is has been made in the field of the organocatalyzed/promoted
regenerated (Scheme 142).333 It was thought that the hydrogen aziridination of olefins, particularly electron-deficient ones,336f
bonding between the substrate and the peptide catalyst played a which will be discussed in this section.
crucial role in the enantioselectivity. Only 16% ee was obtained 3.1. Chiral Quaternary Ammonium Salt-Catalyzed
when the proline peptide bond of 738 was replaced by an olefin Aziridination
isostere (739) (Figures 94 and 95). The ee increased to 52% by Cinchona alkaloid-derived quaternary ammonium salts have
introducing a fluorine atom to the alkene (740) (Figure been used as phase-transfer catalysts for the asymmetric
95).333b Miller and co-workers subsequently showed that aziridination of electron-deficient olefins. In 1996, Prabhakar
aspartic acid-based peptides 744 and 745 were effective and co-workers reported that up to 61% ee was obtained for
catalysts for the site-selective epoxidation of polyenes.335 As aziridination of methyl acrylate with ammonium salt 13b as
shown in Figure 96, the 2,3-olefin was regio- and catalyst and N-aryl hydroxamic acids 751 as nitrogen sources
enantioselectively epoxidized with catalyst 744 to give the (Figures 97 and 98).337 In 2005, Murugan and co-workers
epoxide in up to 93% ee. Notably, in the case of showed that up to 95% ee could be achieved for aziridination of
Figure 97. Quaternary ammonium salt catalysts 13b and 746−750.
tert-butyl acrylate with ammonium salt catalysts 746 and 747

(Figures 97 and 98).338
Figure 100. Aziridination of olefins with catalyst 749 or 750.
Figure 101. Chiral amines 754−756.
102). The amine promoter could be used in a catalytic amount.

In their studies, Armstrong and co-workers showed that up to
Figure 98. Aziridination of olefins with quaternary ammonium salt

catalysts.
In 2004, Fioravanti, Pellacani, Tardella, and co-workers

showed that up to 75% ee could be obtained for aziridination of
2-phenylsulfanyl-substituted cyclic enones with ammonium
salts 13b and 748 (Figure 97) using NsONHCO2Et (752) as
the nitrogen source (Figure 99).339 Minakata and co-workers
Figure 102. Asymmetric aziridination of chalcones using chiral amines

Figure 99. Aziridination of cyclic enones with catalyst 13b or 748. 754−756.
employed N-chloro-N-sodiocarbamates 753 as nitrogen sources

56% ee could be obtained for aziridination using quinine (755)
for asymmetric aziridination of α,β-unsaturated amides, giving
and O-(diphenylphosphinyl)hydroxylamine (DppONH2) (Fig-
up to 87% ee with ammonium salt catalysts 749 and 750
ures 101 and 102).343 Page and co-workers investigated the
(Figures 97 and 100).340 High diastereoselectivities (up to
asymmetric aziridination of chalcone with binaphthalene-based
>99:1 dr) were achieved for substrates bearing chiral auxiliaries
chiral amines and MSH or DppONH2 as N-transfer agent,
(Figure 100).341
achieving 37% ee with amine 756 (Figures 101 and 102).344
3.2. Amine-Promoted Aziridination via Aminimide A possible catalytic cycle for the amine-promoted aziridina-
In 2006, Shi and co-workers reported a chiral amine-promoted tion is shown in Scheme 143. The tertiary amine R3N first
asymmetric aziridination of chalcones with O-mesitylenesulfo- reacts with O-substituted hydroxylamine R′ONH2 to form the
nylhydroxylamine (MSH) as the NH source in the presence of hydrazinium salt (757), which is deprotonated by a base to
a base such as CsOH·H2O.342 NH aziridines were obtained in generate the aminimide intermediate (758). The aminimide
up to 67% ee with (+)-Tröger’s base (754) (Figures 101 and then undergoes conjugate addition to the electron-deficient
Scheme 143. Proposed Mechanism for the Amine-Promoted aziridinated in 69−86% yield and up to 90% ee with amine
Aziridination of Olefins catalyst 137 and TsNHOTs (764) (Figure 104).346
Figure 104. Aziridination of α-branched enals catalyzed by 137.
The proposed mechanism for the asymmetric aziridination is

shown in Scheme 145. The amine catalyst first reacts with the
olefin followed by ring closure to give the aziridine and Scheme 145. Proposed Mechanism for the Chiral Amine-
regenerate the tertiary amine.342,343 Catalyzed Aziridination of Enals
3.3. Aziridination via Iminium/Enamine Catalysis
3.3.1. Pyrrolidine-Based Catalysts. Asymmetric aziridi-
nation of α,β-unsaturated aldehydes has been achieved with
chiral secondary amine catalysts. In 2007, Córdova and co-
workers reported that a variety of α,β-unsaturated aldehydes
were effectively aziridinated with diphenylprolinol silyl ether
144 as catalyst and acylated hydroxycarbamates 760−764 as
nitrogen sources, giving the aziridines in high enantioselectiv-
ities (up to 99% ee) (Figure 103).345 The resulting aziridine
enal to form iminium salt intermediate 767, which is then

attacked by the acylated hydroxycarbamate through aza-
conjugate addition to generate enamine intermediate 768.
Upon ring closure, 768 is converted to iminium ion 769, which
is hydrolyzed to give the aziridine and regenerate the amine
catalyst.345
In 2009, Hamada and co-workers reported the asymmetric
aziridination of α,β-unsaturated aldehydes with chiral amine
Figure 103. Aziridination of α,β-unsaturated aldehydes with chiral 189 and BocNHOTs (763). The resulting products were
amine 144. converted to other aziridine derivatives with up to 99% optical
purity via reduction and oxidation (Figure 105).347
Jørgensen and co-workers showed that various optically
active building blocks could be readily prepared via a one-pot
(765) was converted into β-amino acid ester 766 by ring process using chiral amine 137-catalyzed asymmetric aziridina-
opening and concomitant esterification, followed by removal of
the Cbz group (Scheme 144).345a In their studies, Greck, de
Figueiredo, and co-workers showed that α-branched enals were
Scheme 144. Synthesis of β-Amino Acid Ester 766 from

Aziridine 765
Figure 105. Aziridination of α,β-unsaturated aldehydes with chiral

amine 189.

tion of enals 770 as the key step (Scheme 146).117c−g,i They and 773 as catalysts, giving the corresponding aziridines in up
also studied the remote aziridination of cyclic 2,4-dienals with to 99% ee (Figures 107 and 108).349
Scheme 146. One-Pot Synthesis of Various Building Blocks

via Asymmetric Aziridination
Figure 107. Chiral amine salt catalysts.
catalyst ent-137 and nitrogen source BocNHOTs (763) (Figure

106).348 Aziridination occurred regioselectively at the endocy-
Figure 108. Aziridination of enones using chiral amine salt 772 or

773.
Jørgensen and co-workers reported that optically active allylic

amines were readily obtained with 94−99% ee via asymmetric
aziridination of enones using amine salt catalyst 202 and
Figure 106. Aziridination of 2,4-dienals catalyzed by ent-137. TsNHOTs (764), followed by one-pot Wharton reaction
(Figures 107 and 109).134 They also showed that oxazolidi-
clic double bond, giving the aziridines in up to 95% ee. The

aziridine products could be transformed into allylic δ-amino
esters and oxazolidinones (Scheme 147).
3.3.2. Chiral Amine Salt Catalysts. The asymmetric
aziridination has been extended to α,β-unsaturated ketones
with chiral amine salt catalysts. Melchiorre and co-workers
reported that acyclic and cyclic enones were effectively
aziridinated with cinchona alkaloid-derived amine salts 772
Figure 109. One-pot aziridination/Wharton reaction sequence.
Scheme 147. Further Transformations of Aziridines
nones could be obtained with up to 99% ee from enones

through asymmetric aziridination with chiral amine salt 774 and
BocNHOTs (763), followed by double SN2 reaction using NaI
in the same pot (Figures 107 and 110).350
In 2011, Hamada and co-workers showed that chiral diamine
catalyst 775 was effective for asymmetric aziridination of cyclic
enones, giving the corresponding aziridines in 75−91% yield
and 88−97% ee using CbzNHOTs (762) or BocNHOTs
(763) as nitrogen source (Figure 111).351 The resulting chiral
aziridine (776) was elaborated to the key intermediate (780)
toward (−)-agelastatin A (781) (Scheme 148).351
Figure 110. One-pot aziridination/double SN2 reaction sequence.
Figure 112. Aziridination of olefins with chiral amino thiourea catalyst

782.
Scheme 149. Synthesis of α,α-Disubstituted-α-amino Acid

Ester 786
catalysts such as chiral guanidines and chiral β-amino alcohols

Figure 111. Aziridination of cyclic enones with diamine catalyst 775. have proven very effective for electron-deficient α,β-unsaturated
carbonyl substrates (mostly α,β-unsaturated ketones), obtain-
Scheme 148. Synthesis of the Key Intermediate (780) ing high selectivities. Chiral amine-catalyzed epoxidation via
toward (−)-Agelastatin A (781) iminium ion/enamine pathway has expanded the nucleophilic
epoxidation to α,β-unsaturated aldehydes in addition to α,β-
unsaturated ketones. A major advancement in electrophilic
asymmetric epoxidation has been achieved with chiral ketone
catalysts. Researchers from a number of laboratories have
investigated a wide variety of structurally diverse ketone
catalysts including C2-symmetric-, ammonium-, bicyclic-,
carbocyclic-, and carbohydrate-derived ketone catalysts and
obtained impressive results. Chiral iminium salts have also
shown to be effective epoxidation catalysts, achieving high
enantioselectivities for certain olefin classes and requiring very
low catalyst loading. Chiral amine salts provide interesting
potential systems for asymmetric epoxidation. Additionally,
3.4. Chiral Amino Thiourea-Catalyzed Aziridination aspartic acid-based peptide catalysts have demonstrated highly
Chiral bifunctional amino thioureas can also be used as catalysts promising results for asymmetric epoxidation of olefins. Among
for aziridination of electron-deficient olefins. In 2012, Lattanzi these systems, readily available fructose-derived ketone 268
and co-workers reported that α-acyl acrylates were aziridinated (Figure 70) has been shown to be highly enantioselective,
in up to 82% ee with catalyst 782 and BocNHOTs (763) general, predictable, practical, and scalable. Flexibility in the
(Figure 112).352 It was suggested that the thiourea and amino catalyst design has allowed variations to be synthesized in order
groups of the catalyst activate the substrate and nucleophile, to address various steric and electronic needs of substrates,
respectively. As shown in Scheme 149, the resulting aziridine further broadening the generality of this class of catalyst. The
(784) could be readily converted to α,α-disubstituted-α-amino ease of use and effectiveness of catalyst 268 has been
acid ester 786 in high yield. documented in its synthetic applications. Its versatility has
also been shown in the epoxidation of polyunsaturated systems,
4. CONCLUSION being able to indiscriminately provide polyepoxides rapidly or
Organocatalytic asymmetric epoxidation of olefins has discriminately by selectively epoxidizing a certain olefin class via
witnessed exponential growth during the last few decades. As sterics and/or electronics. Epoxidation with ketone 268
shown in this review, significant contributions from various displayed unprecedented generality and practicality for non-
research groups have obtained remarkable results for metal systems at the time, which opened up new perspectives
asymmetric epoxidation of olefins. Systems including phase- for practical asymmetric reactions using simple chiral, organic
transfer catalysts, peptide catalysts, and bifunctional base molecules as catalysts and contributed greatly to the revital-
ization of the yet-to-be termed field of “organic catalysis” or

“organocatalysis”.
Significant progress has also been made for organocatalyzed
asymmetric aziridination of electron-deficient olefins using
catalysts such as cinchona alkaloid-derived quaternary ammo-
nium salts, chiral amines, and amine salts as well as amino
thioureas. High enantioselectivities have been obtained in
various cases, which provides promising results for future
development and application in this field.
Despite the extensive research presented herein, there
continues to be a need for more selective and robust catalysts Qian Wang was born in Gansu, China. She received her B.Sc. degree in
Chemical Engineering from Tsinghua University in 2008 and Ph.D.
to accomplish the challenging incorporation of oxygen and degree from the Tokyo Institute of Technology in 2012 under the
nitrogen into organic frameworks. As asymmetric organic supervision of Professor Yuichi Kobayashi. She joined Colorado State
University as a postdoctoral fellow with Professor Yian Shi in 2012.
synthesis continues to mature and evolve, catalytic enantiose-
lective epoxidation and aziridination of olefins is sure to be at
the forefront.
AUTHOR INFORMATION
Corresponding Author
*E-mail: yian@lamar.colostate.edu.
Notes
The authors declare no competing financial interest.
Biographies
Richard G. Cornwall was born in Bloomington, IN. He received his

B.Sc. degree in Chemistry and a B.A. degree in German from Arizona
State University in 2008. He is currently a graduate student at
Colorado State University with Professor Yian Shi, studying
development of novel synthetic methodologies and asymmetric
catalysis.
Yingguang Zhu was born in Hunan, China. He received his B.Sc.

degree from Hunan University of Science and Technology in 2002 and
M.Sc. degree from East China Normal University in 2005. After 2
years working at WuXi AppTec Co., Ltd. (China) as a research
scientist, he went on to obtain his Ph.D. degree from East China
Yian Shi was born in Jiangsu, China. He obtained his B.Sc. degree from
Normal University in 2010 under the supervision of Professors Nanjing University in 1983, M.Sc. degree from the University of
Toronto with Professor Ian W. J. Still in 1987, and Ph.D. degree from
Wenhao Hu and Liping Yang. He joined Colorado State University as
Stanford University with Professor Barry M. Trost in 1992. After a
a postdoctoral fellow with Professor Yian Shi in 2010. His current postdoctoral study at Harvard Medical School with Professor
Christopher Walsh, he joined Colorado State University as an
research interests include development of novel synthetic method-
Assistant Professor in 1995 and was promoted to Associate Professor
ologies and asymmetric synthesis. in 2000 and Professor in 2003. His current research interests include

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Organocatalytic Asymmetric Epoxidation and Aziridination of Olefins and Their Synthetic Applications

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Review

Organocatalytic Asymmetric Epoxidation and Aziridination of Oleﬁns

2.1.1. Cinchona Alkaloid-Derived Quaternary Ammo-

Asymmetric catalysis using metals has seen widespread

Scheme 3. Synthesis of Palmarumycin C2 (10) and

Figure 7. Epoxidation of enones with catalysts 14−16.

catalysts. Up to 84% ee was obtained for epoxidation of 2-

entry Ar1 Ar2 yield (%) dr ee (major) (%)

Table 2. Epoxidation of β,β-Disubstituted Enones with

enones with catalyst 21b using KOCl as oxidant (Figure

Figure 8. Proposed transition state for epoxidation using catalyst 18.

nium salts with the C-9 hydroxyl groups being protected as

Figure 11. Epoxidation of enones with catalyst 21b and KOCl.

other useful synthetic intermediates such as α,β-epoxy esters

Scheme 6. Transformations of α,β-Epoxy Ketone

Figure 16. Quaternary ammonium salt catalysts 25 and 26.

which achieved up to 63% ee in the epoxidation of

Figure 13. Epoxidation of chalcones with catalyst 21b and TCCA.

oxidant.29b Catalyst 21b was also used for epoxidation of α,β-

Figure 14. Quaternary ammonium salt catalysts 23 and 24.

to 78% ee was obtained for epoxidation of 1,3-diarylenones

Figure 22. Crown ether-type phase-transfer catalysts 36−38.

catalysts 36 and 37 for the epoxidation,43 aﬀording up to

epoxidation of (E)-chalcone (9.1% ee) with pyrrolidinium salts

Figure 23. Epoxidation of enones with crown ether-type catalysts.

Both the monosaccharide moiety and the nitrogen substituent

Scheme 8. Synthesis of Poly-Oxygenated α-

Scheme 9. Synthesis of Dihydroﬂavonol 50

Figure 24. Epoxidation of oleﬁns with polypeptide catalysts 41−43.

Figure 24). The polypeptide catalysts can be synthesized via

Scheme 11. Synthesis of SK&F 104353 (55)

and catalyst loading.59 The modiﬁed epoxidation process was

Figure 27. Epoxidation of oleﬁns with polypeptide catalyst under PTC

2004, Roberts and co-workers reported their studies on the

Figure 26. Epoxidation of various electron-deﬁcient oleﬁns with

As shown by Falck and co-workers in 1997, stannyl-

Figure 30. Epoxidation of chalcones with silica-grafted poly-L-leucine.

The synthetic applications of the epoxidation using silica-

Scheme 13. Synthesis of Tetrahydroquinolone 63

diol 67 was obtained from epoxy ketone 65 via oxime

Scheme 20. Synthesis of Diltiazem Hydrochloride (91)

antiamnaesic agent with potent hepatoprotective activity)

Scheme 21. Synthesis of (+)-Clausenamide (94)

Scheme 17. Synthesis of Galactonic Acid Derivative 79

Scheme 22. Synthesis of (S)-Fenoprofen (97) and (S)-

Scheme 18. Synthesis of (+)-Goniopypyrone (84) and

Imidazolium-attached polypeptides have also been inves-

Figure 31. Epoxidation of chalcones with imidazolium-modiﬁed poly-

Figure 33. Epoxidation of chalcone with soluble peptide catalysts.

reactor. After the epoxide and unreacted chalcone were passed

aminoisobutyric acid (Aib) using urea−H2O2 and DBU in

Scheme 23. Epoxidation of Chalcone with Soluble Peptide

Figure 34. Epoxidation of enones with peptide catalyst 106.

promoted formation of a helical structure as well as enhanced

Scheme 24. Epoxidation of Chalcone with Catalyst 109 or

with the N-terminal amidic N−H groups. The helical

Figure 36. Epoxidation of enals with polypeptide catalyst 108.

Pathway I was shown to be kinetically favored over pathway

Figure 40. β-Amino alcohol catalysts.

Scheme 26. Epoxidation of Quinone 124 Using Guanidine

Figure 41. Epoxidation of enones with amino alcohol catalysts 125−

Scheme 27. Proposed Mechanism for Epoxidation of Enones

Figure 38. Epoxidation of enones with guanidine catalysts 116−123.

and co-workers subsequently showed that the reactivity and